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The Seaweed Gatherers, Paul Gaugin
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Iodine Research
Resource Network of The Iodine Movement
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Iodine and the Body
Breast pg 5 (cont)
SARAIVA
Profile of thyroid hormones in breast cancer patients.
Saraiva PP, Figueiredo NB, Padovani CR, Brentani MM, Nogueira CR.
Braz J Med Biol Res. 2005 May;38(5):761-5. Epub 2005 May 25.
Estrogen involvement in breast cancer has been established; however, the association between breast cancer
and thyroid diseases is controversial. Estrogen-like effects of thyroid hormone on breast cancer cell growth in
culture have been reported. The objective of the present study was to determine the profile of thyroid hormones in
breast cancer patients.
Serum aliquots from 26 patients with breast cancer ranging in age from 30 to 85 years and age-matched normal
controls (N = 22) were analyzed for free triiodothyronine (T3F), free thyroxine (T4F), thyroid-stimulating hormone
(TSH), antiperoxidase antibody (TPO), and estradiol (E2). Estrogen receptor ss (ERss) was determined in tumor
tissues by immunohistochemistry.
Thyroid disease incidence was higher in patients than in controls (58 vs 18%, P < 0.05). Subclinical
hyperthyroidism was the most frequent disorder in patients (31%); hypothyroidism (8%) and positive anti-TPO
antibodies (19%) were also found. Subclinical hypothyroidism was the only dysfunction (18%) found in controls.
Hyperthyroidism was associated with postmenopausal patients, as shown by significantly higher mean T3 and
T4 values and lower TSH levels in this group of breast cancer patients than in controls. The majority of positive
ERss tumors were clustered in the postmenopausal patients and all cases presenting subclinical
hyperthyroidism in this subgroup concomitantly exhibited Erss-positive tumors. Subclinical hyperthyroidism was
present in only one of 6 premenopausal patients.
We show here that postmenopausal breast cancer patients have a significantly increased thyroid hormone/E2
ratio (P < 0.05), suggesting a possible tumor growth-promoting effect caused by this misbalance.
SEKIYA
Intracellular signaling in the induction of apoptosis in a human breast cancer cell line by water extract of Mekabu.
Sekiya M, Funahashi H, Tsukamura K, Imai T, Hayakawa A, Kiuchi T, Nakao A.
Int J Clin Oncol. 2005 Apr;10(2):122-6.
BACKGROUND: We previously reported that water extract of Mekabu, a kind of seaweed, induced apoptosis in a
human breast cancer cell line. In the present study we investigated intracellular signaling in apoptosis, with a
focus on caspases.
METHODS: Mekabu extract, obtained with ultrapure water, was used to induce apoptosis in a human breast
cancer cell line, MDA-MB231, and DNA fractionation was investigated by flow cytometry and electrophoresis. In
addition, using the caspase detection kit Caspa Tag, activation of caspases 3, 6, 8, and 9 was observed under a
fluorescence microscope. Furthermore, using antibodies to caspases 3, 8, 9, and Bid, we conducted a protein
analysis by Western blotting to determine the activation of these substances.
RESULTS: Obvious ladder formation demonstrating DNA fractionation was seen, confirming that Mekabu extract
induced apoptosis. In the fluorescence microscope observations, activation of caspases 3, 6, and 8, but not
caspase 9, was seen. Activated caspases 3 and 8 were detected in the Western blotting analysis, but no proteins
of activated caspase 9 or Bid were detected.
CONCLUSION: Mekabu extract activates caspases 3, 6, and 8 and contributes to intracellular signaling to induce
apoptosis in a human breast cancer cell line. This signaling is not via the mitochondria.
SHRIVASTAVA
Molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells involving
mitochondria-mediated pathway.
Shrivastava A, Tiwari M, Sinha RA, Kumar A, Balapure AK, Bajpai VK, Sharma R, Mitra K, Tandon A, Godbole MM
J Biol Chem. 2006 Jul 14;281(28):19762-71. Epub 2006 May 5.
Molecular iodine (I(2)) is known to inhibit the induction and promotion of N-methyl-n-nitrosourea-induced
mammary carcinogenesis, regresses 7, 12-Dimethylbenz (a)-anthracene-induced breast tumors in rat and has
also shown beneficial effect in the fibrocystic human breast disease. Cytotoxicity of iodine on cultured human
breast cancer cell lines viz. MCF-7, MDA-MB-231, MDA-MB-453, ZR-75-1 and T-47D is reported in this
communication. Iodine induces apoptosis in all the cell lines tested, except MDA-MB-231 shown by sub-G1 peak
analysis using flow cytometry. Iodine inhibited proliferation of normal human peripheral blood mononuclear cells,
however did not induce apoptosis in these cells. Iodine-induced apoptotic mechanism was studied in MCF-7
cells. DNA fragmentation analysis confirmed internucleosomal DNA degradation. Terminal deoxynucleotidyl
transferase-dUTP nick end labeling established that iodine induces apoptosis in time and dose- dependent
manner in MCF-7 cells. Iodine-induced apoptosis is independent of caspases. Iodine dissipates mitochondrial
membrane potential, exhibits an antioxidant activity and causes depletion in total cellular thiol content. Western
blot results showed decrease in Bcl-2 and upregulation of Bax. Immunofluorescence studies confirmed
activation and mitochondrial membrane localization of Bax. Ectopic Bcl-2 overexpression did not rescue iodine-
induced cell death. Iodine treatment induces translocation of Apoptosis inducing factor from mitochondria to the
nucleus. Treatment of N-acetyl-L-cysteine prior to iodine exposure restored basal thiol content, ROS levels and
completely inhibited nuclear translocation of Apoptosis inducing factor and subsequently cell death, indicating
that thiol depletion may play an important role in iodine-induced cell death. These results demonstrate that iodine
treatment activates a caspase-independent and mitochondria-mediated apoptotic pathway.
SKIBOLA
Brown kelp modulates endocrine hormones in female sprague-dawley rats and in human luteinized granulosa
cells.
Skibola CF, Curry JD, VandeVoort C, Conley A, Smith MT.
J Nutr. 2005 Feb;135(2):296-300.
Epidemiological studies suggest that populations consuming typical Asian diets have a lower incidence of
hormone-dependent cancers than populations consuming Western diets. These dietary differences have been
mainly attributed to higher soy intakes among Asians. However, studies from our laboratory suggest that the anti-
estrogenic effects of dietary kelp also may contribute to these reduced cancer rates. As a follow-up to previous
findings of endocrine modulation related to kelp ingestion in a pilot study of premenopausal women, we
investigated the endocrine modulating effects of kelp (Fucus vesiculosus) in female rats and human luteinized
granulosa cells (hLGC)…. These data show endocrine modulating effects of kelp at relevant doses and suggest
that dietary kelp may contribute to the lower incidence of hormone-dependent cancers among the Japanese.
The effect of Fucus vesiculosus, an edible brown seaweed, upon menstrual cycle length and hormonal status in
three pre-menopausal women: a case report.
Skibola CF.
BMC Complement Altern Med. 2004 Aug 4;4:10.
BACKGROUND: Rates of estrogen-dependent cancers are among the highest in Western countries and lower in
the East. These variations may be attributable to differences in dietary exposures such as higher seaweed
consumption among Asian populations. The edible brown kelp, Fucus vesiculosus (bladderwrack), as well as
other brown kelp species, lower plasma cholesterol levels. Since cholesterol is a precursor to sex hormone
biosynthesis, kelp consumption may alter circulating sex hormone levels and menstrual cycling patterns. In
particular, dietary kelp may be beneficial to women with or at high risk for estrogen-dependent diseases. To test
this, bladderwrack was administered to three pre-menopausal women with abnormal menstrual cycling patterns
and/or menstrual-related disease histories.
CASE PRESENTATION: Intake of bladderwrack was associated with significant increases in menstrual cycle
lengths, ranging from an increase of 5.5 to 14 days. In addition, hormone measurements ascertained for one
woman revealed significant anti-estrogenic and progestagenic effects following kelp administration. Mean
baseline 17beta-estradiol levels were reduced from 626 +/- 91 to 164 +/- 30 pg/ml (P = 0.04) following 700 mg/d,
which decreased further to 92.5.0 +/- 3.5pg/ml (P = 0.03) with the 1.4 g/d dose. Mean baseline progesterone
levels rose from 0.58 +/- 0.14 to 8.4 +/- 2.6 ng/ml with the 700 mg/d dose (P = 0.1), which increased further to
16.8 +/- 0.7 ng/ml with the 1.4 g/d dose (P = 0.002).
CONCLUSIONS: These pilot data suggest that dietary bladderwrack may prolong the length of the menstrual
cycle and exert anti-estrogenic effects in pre-menopausal women. Further, these studies also suggest that
seaweed may be another important dietary component apart from soy that is responsible for the reduced risk of
estrogen-related cancers observed in Japanese populations. However, these studies will need to be performed
in well-controlled clinical trials to confirm these preliminary findings.
SMYTH
Role of iodine in antioxidant defense in thyroid and breast disease.
Smyth PP.
Biofactors. 2003;19(3-4):121-30. Review.
The role played in thyroid hormonogenesis by iodide oxidation to iodine (organification) is well established.
Iodine deficiency may produce conditions of oxidative stress with high TSH producing a level of H2O2, which
because of lack of iodide is not being used to form thyroid hormones. The cytotoxic actions of excess iodide in
thyroid cells may depend on the formation of free radicals and can be attributed to both necrotic and apoptotic
mechanisms with necrosis predominating in goiter development and apoptosis during iodide induced involution.
These cytotoxic effects appear to depend on the status of antioxidative enzymes and may only be evident in
conditions of selenium deficiency where the activity of selenium containing antioxidative enzymes is impaired.
Less compelling evidence exists of a role for iodide as an antioxidant in the breast. However the Japanese
experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet.
Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is
breast specific and its possible relationship to iodine or selenium status awaits resolution.
Iodine can react with double bonds on lipids such as polyunsaturated fatty acids rendering them less reactive to
ROS. Polyunsaturated fatty acids such as arachidonic acid which is known to play a role in intracellular signalling
in the thyroid contains four double bonds and can be easily oxidised and thus contribute to increased lipid
peroxidation [32]. It has been postulated that formation of iodolipids such as iodolactones or iodoaldehydes
represents a form of thyroidal autoregulation [33] which may be the mode of action of iodide inhibition of thyroidal
function in the Wolff-Chaikoff effect [6,34,35]. While lower doses of iodide are necessary substrates for TPO
mediated conversion into I2, iodinated compounds (so called XI) at high doses may exert inhibitory effects on
adenylate-cyclase, NADPH-oxidase and TPO activities [6,35]. This effect seems to require oxidation of I− to I2 as
inhibitors of TPO or I− trapping can reverse the inhibitory effect [35].
A role for iodide as an antioxidant possibly through a protective action of iodolipids as described for the thyroid
has been suggested [64–66]. This is on the basis of a shared iodide concentrating mechanism in both thyroid
and breast as well as a requirement for an iodide oxidation system to provide for the formation of iodoamino
acids leading to thyroid hormone formation in the thyroid and to iodinated milk proteins by the breast necessary
for neonatal nutrition [50–52]. Figure 3 shows in cartoon form the uptake of I− by the breast and its incorporation
into iodoproteins. When taken into the breast I− is incorporated into lactoproteins presumably as a result of
organification into I2 by lactoperoxidases [57,66]. These iodoproteins together with free I− are secreted in breast
milk. As mentioned elsewhere in this communication, I− may also be incorporated into iodolipids such as
iodolactones or iodoaldehydes which in the thyroid have been shown to possess antiproliferative properties. To
date there is no evidence that a similar effect is produced in the breast.
The thyroid, iodine and breast cancer.
Smyth PP.
Breast Cancer Res. 2003;5(5):235-8. Epub 2003 Jul 29.
A renewal of the search for a link between breast cancer and thyroid disease has once again demonstrated an
increased prevalence of autoimmune thyroid disease in patients with breast cancer. This is the most recent of
many studies showing an association between a variety of thyroid disorders and breast cancer. Such an
association is not surprising as both diseases are female predominant with a similar postmenopausal peak
incidence. The significance of the presence of thyroid autoantibodies, particularly thyroid peroxidase antibodies,
in serum from patients with breast cancer is unknown, but it has been suggested that antibody positivity is
associated with better prognosis. One area in which thyroid and breast functions overlap is in the uptake and
utilization of dietary iodide. Experimental findings showing the ability of iodine or iodine-rich seaweed to inhibit
breast tumour development is supported by the relatively low rate of breast cancer in Japanese women who
consume a diet containing iodine-rich seaweed. However, there is as yet no direct evidence that iodine, iodinated
compounds, or a combination of iodine and selenium is the antimammary carcinogenic element in the
Japanese diet. It remains to be resolved whether the perceived breast cancer-thyroid disease relationship is
thyroid or iodine related or, in the case of thyroid autoantibodies, is the consequence of an immune response to
the carcinoma. Is this response breast specific and does it relate to iodine status? These and many other
questions await resolution before a definitive role in the natural history of breast carcinoma can be assigned to
the thyroid.
Tissue iodine content and serum-mediated 125I uptake-blocking activity in breast cancer.
Kilbane MT, Ajjan RA, Weetman AP, Dwyer R, McDermott EW, O'Higgins NJ, Smyth PP.J Clin Endocrinol Metab.
2000 Mar;85(3):1245-50.
In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in
the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2
of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total
tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher
than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal
tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I
uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49
(16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched
female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide
uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly
associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in
those with benign breast disease, once again suggesting an association between thyroid autoimmunity and
breast carcinoma.
Autoimmune thyroid disease and breast cancer: a chance association?
Smyth PP.
J Endocrinol Invest. 2000 Jan;23(1):42-3. Review.
[citation only]
Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma.
Smyth PP, Shering SG, Kilbane MT, Murray MJ, McDermott EW, Smith DF, O'Higgins NJ.
J Clin Endocrinol Metab. 1998 Aug;83(8):2711-6.
The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast
carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was
studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma,
compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease,
compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast
carcinoma demonstrated that TPO.Ab titres > or = 0.3 U/mL were associated with a significantly better disease-
free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were
TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid
volumes within the intermediate range (10.1-18.8 mL) and did not further enhance the good outcome recorded
when volumes were < or = 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and
thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free
survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status
or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a
beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a
biological link between breast carcinoma and thyroid disease.
The thyroid and breast cancer: a significant association?
Smyth PP.
Ann Med. 1997 Jun;29(3):189-91.
[abstract only]
The coincidence of thyroid disorders and breast cancer has long been a subject of debate. Associations with
hyperthyroidism, hypothyroidism, thyroiditis and nontoxic goitre have been reported. Although no convincing
evidence exists of a causal role for overt thyroid disease in breast cancer, the preponderance of published work
favours an association with hypothyroidism. Geographical variations in the incidence of breast cancer have been
attributed to differences in dietary iodine intake and an effect of iodide on the breast has been postulated. Recent
reports have shown a direct association between thyroid enlargement, as assessed by ultrasound, and breast
cancer. Although the exact mechanism for the demonstrated association between diseases of the thyroid and
breast cancer remains to be elucidated, there is at least the possibility that the presence of thyroid abnormalities
may influence breast cancer progression and this alone should stimulate awareness into the coincidence of the
two disorders.
A direct relationship between thyroid enlargement and breast cancer.
Smyth PP, Smith DF, McDermott EW, Murray MJ, Geraghty JG, O'Higgins NJ.
J Clin Endocrinol Metab. 1996 Mar;81(3):937-41.
[abstract only]
Despite extensive study, evidence to support a direct relationship between diseases of the thyroid and breast has
not been established. In this study thyroid volume was assessed by ultrasound in 200 patients with breast
cancer and 354 with benign breast disease. Results were compared to appropriate female control groups. Both
mean thyroid volume (21.1 +/- 1.4 mL) and the percentage of individual patients with enlarged (> 18.0 mL) thyroid
glands (41.5%) were significantly greater in the breast cancer group than equivalent values (13.2 +/- 0.5 mL and
10.5%, respectively) in age-matched controls (P < 0.01 in both cases). The mean thyroid volume of 14.5 +/- 0.34
mL in patients with benign breast disease was also significantly greater than that of 12.5 +/- 0.38 mL in younger
controls (P < 0.01). The results support a direct association between breast cancer and increased thyroid volume
as mean thyroid volumes and the percentage of individual patients with enlarged thyroid glands were similar in
those studied both before (20.8 +/- 1.3 mL and 43.0%) and after (21.4 +/- 1.6 mL and 40.0%) therapies for breast
cancer. Although there is no evidence that thyroid enlargement represents a risk factor for breast cancer, the
results emphasize the importance of raising the consciousness of the coincidence of both disorders.
SPITZWEG
Mammary radioiodine accumulation due to functional sodium iodide symporter expression in a benign
fibroadenoma.
Berger F, Unterholzner S, Diebold J, Knesewitsch P, Hahn K, Spitzweg C.
Biochem Biophys Res Commun. 2006 Nov 3;349(4):1258-63. Epub 2006 Sep 7.
[abstract only]
The sodium iodide symporter (NIS) has been characterized to mediate the active transport of iodide not only in
the thyroid gland but also in various non-thyroidal tissues, including lactating mammary gland and the majority of
breast cancers, thereby offering the possibility of diagnostic and therapeutic radioiodine application in breast
cancer. In this report, we present a 57-year-old patient with multifocal papillary thyroid carcinoma, who showed
focal radioiodine accumulation in a lesion in the right breast on a posttherapy (131)I scan following radioiodine
therapy. CT and MR-mammography showed a focal solid lesion in the right breast suggestive of a fibroadenoma,
which was confirmed by histological examination. Immunostaining of paraffin-embedded tumor tissue sections
using a human NIS antibody demonstrated NIS-specific immunoreactivity confined to epithelial cells of mammary
ducts. In conclusion, in a thyroid cancer patient we identified a benign fibroadenoma of the breast expressing
high levels of functionally active NIS protein as underlying cause of focal mammary radioiodine accumulation on
a posttherapy (131)I scan. These data show for the first time that functional NIS expression is not restricted to
lactating mammary gland and malignant breast tissue, but can also be detected in benign breast lesions, such
as fibroadenomata of the breast.
Dexamethasone stimulation of retinoic Acid-induced sodium iodide symporter expression and cytotoxicity of 131-I
in breast cancer cells.
Unterholzner S, Willhauck MJ, Cengic N, Schutz M, Goke B, Morris JC, Spitzweg C.
J Clin Endocrinol Metab. 2006 Jan;91(1):69-78. Epub 2005 Oct 18.
[abstract only]
CONTEXT: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as
lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-
positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which
might offer the potential to treat breast cancer with radioiodine.
OBJECTIVE: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS
expression and therapeutic efficacy of 131-I in MCF-7 cells.
DESIGN: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern
and Western blot analysis after incubation with Dex (10(-9) to 10(-7) m) in the presence of atRA (10(-6) m) as well
as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity
was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro
clonogenic assay.
RESULTS: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up
to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide
accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after
stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of
131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-
7 cells treated with Dex in the presence of atRA.
CONCLUSION: Treatment with Dex in the presence of atRA significantly increases functional NIS expression
levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7
breast cancer cells.
STRUM
Autoradiographic evidence of a loss of iodination within hormone-dependent GR mouse mammary tumors as
they progress to independence.
Strum JM.
Anat Rec. 1982 Dec;204(4):323-32.
[abstract only]
The purpose of this study was to determine by use of light- and electron-microscope autoradiography whether or
not iodination occurred in mammary tumors of female GR mice. Of the sixty tumors studied it was found that
pregnancy-dependent and hormone-induced tumors possessed iodinating ability. Although mammary glands
from nonpregnant GR mice lacked the ability to iodinate, by the 16th day of pregnancy in response to hormonal
stimulation the glands readily iodinated casein, and some epithelial cells contained ultrastructural cytochemical
evidence of mammary peroxidase. Preneoplastic mammary gland lesions known as hyperplastic alveolar
nodules were also able to iodinate, as were plaques, the disc-shaped lesions which give rise to the hormone-
responsive mammary tumors in this strain. Plaques also contained epithelial cells with mammary peroxidase
activity. When hormone-induced mammary tumors were transplanted into syngeneic mice they retained the ability
to iodinate for several generations. However, as the tumors progressed to hormone independence, the ability to
iodinate was gradually lost. Hormone-independent mammary tumors from GR mice lacked both iodinating ability
and cytochemical evidence of mammary peroxidase. These findings suggest that iodination depends upon
hormone-responsive cells within the mammary tumors and that as these cells become hormone unresponsive,
the ability to iodinate is lost.
Effect of iodide-deficiency on rat mammary gland.
Strum JM.
Virchows Arch B Cell Pathol Incl Mol Pathol. 1979 May 31;30(2):209-20.
When rats are kept iodide-deficient, atrophy and necrosis takes place in the mammary gland and areas of
dysplasia and atypia are seen. Administration of estradiol to iodide-deficient rats stimulates cell division in the
gland and leads to the formation of alveoli. Continued stimulation by estradiol produces changes in the newly-
formed alveolar cells. Their nucleoli are altered and show a separation of components. Ribosomes and lipid
droplets increase and the cells synthesize large vacuoles containing protein. The secretion of great quantities of
this material into areas of the tissue where regressive changes have occurred undoubtedly contributes to the
formation of cysts within the gland. The present findings indicate that iodide-deficiency alters the structure and
function of mammary gland alveolar cells and makes them highly sensitive to stimulation by estradiol.
Site of iodination in rat mammary gland.
Strum JM.
Anat Rec. 1978 Oct;192(2):235-44.
The ability of the mammary gland to take up and organically bind radioiodide was studied in non-pregnant,
pregnant, and lactating rats. Autoradiography was used to determine whether duct cells or alveolar cells are
responsible for iodination in the rat mammary gland. Iodination was not detected in mammary glands from non-
pregnant rats, but occurred late in the twelfth day of gestation and continued throughout pregnancy and lactation.
Protein-containing vacuoles in alveolar cells and casein-like proteins in milk were the major sites where
iodination occurred within the gland. Milk proteins in the lumens of ductules adjacent to alveoli were also
iodinated. In contrast, ducts, myoepithelial cells, fat cells, blood vessels and other histological components of the
gland did not show iodinating capability. Cytochemistry was also used to identify endogenous mammary
peroxidase activity in the same glands, and it was found that the presence and location of this enzyme was
correlated with the ability to iodinate.
TAZEBAY
Unliganded estrogen receptor-alpha activates transcription of the mammary gland Na+/I- symporter gene.
Alotaibi H, Yaman EC, Demirpence E, Tazebay UH.
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1487-96. Epub 2006 May 15.
The function of sodium iodide symporter (Na(+)/I(-) symporter, or NIS) in mammary epithelial cells is essential for
the accumulation of I(-) in milk; the newborn's first source of I(-) for thyroid hormone synthesis. Furthermore,
increased mammary gland NIS expression has previously been shown in human breast cancer. Several
hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using
breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-
alpha (ERalpha) positive cells and we investigated the role of ERalpha in the regulation of NIS expression. We
showed that the suppression of endogenous ERalpha by RNA interference downregulates NIS expression in
ERalpha positive mammary cells. Besides, in an ERalpha negative cell line, reintroduction of ERalpha resulted
in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive
element in the promoter region of NIS that specifically binds ERalpha and mediates ERalpha-dependent
activation of transcription. Our results indicate that unliganded ERalpha (apo-ERalpha) contributes to the
regulation of NIS gene expression.
The mammary gland iodide transporter is expressed during lactation and in breast cancer.
Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG,
Carrasco N.
Nat Med. 2000 Aug;6(8):871-8.
The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By
exploiting this activity, radioiodide has been used for decades with considerable success in the detection and
treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the
mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland
and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland
sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice
bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of
the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared
with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the
mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide
should be studied as a possible option in the diagnosis and treatment of breast cancer.
Besides the thyroid, active iodide transport occurs in the lactating mammary gland, salivary glands and gastric
mucosa. Iodide concentrated in lactating mammary gland and secreted into milk is used by the nursing newborn
for the biosynthesis of thyroid hormones.... The mammary gland iodide transporter was the essential link in the
chain of events that led to a higher thyroid cancer incidence in the aftermath of the Chernobyl power plant
accident. I-131 in radioactive fallout was accumulated by cattle in milk, and children who ingested I-131
contaminated milk subsequently concentrated I-131 in their thyroids through the thyroid NIS, exposing the gland
to tumorigenic doses of radiation.
Effects of hormones on mgNIS [mammary gland NIS] expression in ovariectomized mice. We administered 17-B-
estradiol, progesterone, oxytocin, and prolactin, both individually and in different combinations, to nubile
ovariectomized adult mice and assessed mgNIS expression in mammary tissue. Administration of oxytocin
alone to ovariectomized mice did not cause an increase in mgNIS expression.... Of all the hormones tested
individually, only 17-B-estradiol led to a clearly discernible increase in mgNIS expression.... The upregulating
effect of oxytocin on mgNIS expression may require estrogen.
The greatest increase in mgNIS expression occurred after administration of 17-B-estradiol, oxytocin and prolactin
together.... When progesterone was added to the 17-B-estradiol-oxytocin-prolactin combination, mgNIS
expression was substantially decreased. Conversely, a comparison of mgNIS expression in mice treated with
estrogen or estrogen plus progesterone showed that progesterone did not interfere with 17-B-estradiol
enhancement of mgNIS expression. In conclusion, the combination of estrogen, prolactin and oxytocin (in the
absence of progesterone) led to the highest levels of mgNIS expression in ovariectomized mice. This
combination of hormones closely resembles the relative hormonal levels in mice and rats during lactation.
More than 80% of the breast cancer specimens analyzed expressed mgNIS, in contrast to no expression in
normal tissues from reductive mammoplasties, indicating that mgNIS is unregulated with a high frequency
during malignant transformation in human breast.
A threshold level of circulating estrogens seemed to be necessary for optimal mgNIS expression overall, and in
particular for the upregulation of mgNIS by oxytocin. The cooperative function of estrogens in the effect of oxytocin
on mgNIS may be explained by the likelihood that oxytocin receptor mRNA is upregulated by estrogen in the
breast, as it is in the hypothalamus and uterus. Additionally, estrogen may have a direct effect on mgNIS
transcription, as the NIS promoter contains several half-site estrogen-responsive elements.
In intact, nongestational, nonlactating animals, exogenous prolactin would cause endogenous estrogen levels,
which are lower than those in gestational or lactating animals, to decrease below the threshold, preventing
concomitantly administered oxytocin from stimulating mgNIS expression.... In the presence of high levels of
estrogen, prolactin may have a separate direct or indirect stimulatory effect on mgNIS expression by an as yet
unknown mechanism.... During lactation, estrogens would remain above the necessary threshold for oxytocin to
stimulate mgNIS expression and for prolactin to enhance, rather than antagonize, this effect.... The ability of
progesterone to inhibit the combined stimulatory effect of 17-B-Estradiol, oxytocin and prolactin on mgNIS
expression may involve a direct inhibition of oxytocin receptor signaling by competitive binding of progesterone to
the oxytocin receptor in the breast, similar to progesterone's effect in the uterus.
mgNIS expression may also be induced by nonhormonal factors involved in the malignant transformation of
mammary epithelial cells.
TEAS
Breast cancer disparities in South Carolina: early detection, special programs, and descriptive epidemiology.
Adams SA, Hebert JR, Bolick-Aldrich S, Daguise VG, Mosley CM, Modayil MV, Berger SH, Teas J, Mitas M,
Cunningham JE, Steck SE, Burch J, Butler WM, Horner MJ, Brandt HM.
J S C Med Assoc. 2006 Aug;102(7):231-9. Review.
A discrepancy exists between mortality and incidence rates between African-American and European-American
women in South Carolina. The relationship between tumor grade and the estrogen/ progesterone receptor status
is different in African-American and European-American women. African-American women with breast cancer
should be encouraged to participate in clinical trials, with the goal of identifying biological factors that might
facilitate the detection of tumors at an earlier stage and the development of more effective therapies. The most
important of our goals is to design studies to reduce the incidence of the disease and interventions to improve
survival and quality of life. The importance of participation in research cannot be overstated. Reproductive factors
such as early pregnancy and multiple pregnancies are strongly related to breast cancer risk, however, promotion
of these factors as a "prevention strategy," clearly does not lead to cogent, comprehensive public health
messages. Data from ecological and migrant studies point clearly to other factors that may be important such as
diet. Additional research around primary prevention strategies is needed. In addition, yearly mammograms
(secondary prevention) are recommended for women over 50 years old or those with relatives who have
developed breast cancer. The Best Chance Network, as a provider of screenings to low-income, uninsured
women, has helped to narrow the racial gap in screening that otherwise might exist (see Figures 3 and 4) to a
large extent. The determination for timing of surgery after diagnosis needs additional consideration. For example,
factors such as effective screening in younger women, timing of screening and surgery in relationship to the
ovulatory cycle, and season of screening and surgery may have a great impact on outcomes and may offer some
insight into the process of carcinogenesis and therapeutic efficacy. Research into this area is so novel that the
impact on possible ethnic disparities is completely unknown. The South Carolina Cancer Disparities Community
Network (SCCDCN) has identified the following areas as potential research foci: Identification of small media
interventions as an effective strategy to motivate targeted populations, especially those least likely to seek
screening for breast cancer and those least likely to participate in research programs (African-Americans).
Utilization of breast cancer survivors, self-identified as community natural helpers, can share their experiences
with their church congregation. A replication of such a program in South Carolina has great potential because of
the strong presence of the church, especially in rural parts of the state. Programs that closely integrate religion
with screening women for breast cancer are promising in this state. Development of a mammography registry
whereby information on all mammography procedures would be collected within a single database system
(much like a central cancer registry). This would aid in identifying population groups that could be targeted for
special programs and in the examination and exploration of the most appropriate modalities of detection. Such a
resource could also be a useful tool to encourage screening. Thus, this focus area has the potential to benefit
epidemiologic and health promotion research on many different levels. Additional breast cancer screening
methods should not be overlooked as a potential research focus. Mammography is not the only valid screening
method for breast cancer. Magnetic resonance imaging has shown some promise for screening among women
with a genetic predisposition for cancer. Another promising avenue is thermography. Because detection rates
may depend on age, ethnicity, and breast mammographic characteristics, women for whom regular screening
methods do not detect their cancers (e.g. older age, African-American ethnicity, dense breasts) must be identified
and other screening methods promoted within these populations. The above-mentioned mammography registry
would support this type of research.
The macrobiotic diet in cancer.
Kushi LH, Cunningham JE, Hebert JR, Lerman RH, Bandera EV, Teas J.
J Nutr. 2001 Nov;131(11 Suppl):3056S-64S. Review.
Macrobiotics is one of the most popular alternative or complementary comprehensive lifestyle approaches to
cancer. The centerpiece of macrobiotics is a predominantly vegetarian, whole-foods diet that has gained
popularity because of remarkable case reports of individuals who attributed recoveries from cancers with poor
prognoses to macrobiotics and the substantial evidence that the many dietary factors recommended by
macrobiotics are associated with decreased cancer risk. Women consuming macrobiotic diets have modestly
lower circulating estrogen levels, suggesting a lower risk of breast cancer. This may be due in part to the high
phytoestrogen content of the macrobiotic diet. As with most aspects of diet in cancer therapy, there has been
limited research evaluating the effectiveness of the macrobiotic diet in alleviating suffering or prolonging survival
of cancer patients. The few studies have compared the experience of cancer patients who tried macrobiotics with
expected survival rates or assembled series of cases that may justify more rigorous research. On the basis of
available evidence and its similarity to dietary recommendations for chronic disease prevention, the macrobiotic
diet probably carries a reduced cancer risk. However, at present, the empirical scientific basis for or against
recommendations for use of macrobiotics for cancer therapy is limited. Any such recommendations are likely to
reflect biases of the recommender. Because of its popularity and the compelling evidence that dietary factors are
important in cancer etiology and survival, further research to clarify whether the macrobiotic diet or similar dietary
patterns are effective in cancer prevention and treatment is warranted.
Dietary seaweed (Laminaria) and mammary carcinogenesis in rats.
Teas J, Harbison ML, Gelman RS.
Cancer Res. 1984 Jul;44(7):2758-61.
[abstract only]
To test the potential in vivo antitumor effect of dietary seaweed, we induced mammary tumors in female Sprague-
Dawley rats with the carcinogen 7,12-dimethylbenz(a)anthracene. Twenty-one-day-old rats (n = 108) were divided
into two groups. Controls were fed a standard semipurified diet, and experimental rats received the control diet
with 5% Laminaria, a brown seaweed, replacing 5% alphacel . At 55 days of age, each rat received 5 mg 7,12-
dimethylbenz(a)anthracene intragastrically. Rats were palpated for mammary tumors and weighed weekly for 26
weeks. Complete autopsies were then done on all rats. The seaweed diet did not alter weight gain or weights of
body organs at autopsy. Experimental rats had a significant delay in the time to tumor (p = 0.007); median time
until tumor was 19 weeks in experimental rats and 11 weeks in control animals. Among mammary
adenocarcinoma tumor-bearing animals, experimental rats had fewer adenocarcinomas/individual (p less than
0.05). There was also an overall 13% reduction in the number of experimental rats with histologically confirmed
adenocarcinomas (76% among the control rats compared to 63% among the experimental rats). Components of
Laminaria which might account for the observed difference in mammary tumor growth are varied and include the
sulfated polysaccharide fucoidan . Rats in the top row of cages had a significant (p = 0.01) delay in time to tumor
compared to rats in the lower four rows. In each row, the seaweed-fed rats had a longer time to tumor than did
the control rats.
The dietary intake of Laminaria, a brown seaweed, and breast cancer prevention.
Teas J
Nutr Cancer. 1983;4(3):217-22. Review.
[abstract only]
Based on epidemiological and biological data, Laminaria, a brown kelp seaweed, is proposed as an important
factor contributing to the relatively low breast cancer rates reported in Japan. Several possible mechanisms for
the influence of Laminaria on breast cancer are proposed: Laminaria is a source of nondigestible fiber, thereby
increasing fecal bulk and decreasing bowel transit time; it changes the posthepatic metabolism of sterols; it
contains an antibiotic substance that may influence fecal ecology; it contains 1-3 beta glucan, which alters
enzymatic activity of fecal flora; and it stimulates the host-mediated immune response. It is suggested that
Laminaria may play a role in preventing either the initiation of breast cancer or its promotion by endogenous
physiological factors.
The consumption of seaweed as a protective factor in the etiology of breast cancer.
Teas, J
Med Hypotheses. 1981 May;7(5):601-13.
A review of the biological properties of seaweed is presented and the role of seaweed as a breast cancer
anticarcinogen is suggested. Proposed mechanisms of action are: reduction of plasma cholesterol, binding of
biliary steroids, inhibition of carcinogenic fecal flora, binding of pollutants, stimulation of the immune system, and
the protective effects of beta-sitosterols. In an experiment using sarcoma-180 in mice, seaweed extract appeared
to have an antitumor effect. Thus it is suggested that breast cancer may be prevented and that this dietary habit
among the Japanese could be an important factor in understanding the lower breast cancer rates reported in
Japan.
TORREMANTE
Mastopathy, breast cancer and iodolactone [English Translation]
Torremante, P.
Dtsch Med Wochenschr. 2004 Mar 19;129(12):641-5.
Conclusion: A source of nutrition which emphasizes seafood and, thereby, provides a source of polyunsaturated
fatty acids and iodine is a dietary basis for iodolactone formation. This could be the reason for the low incidence
of breast cancer in Japan. Iodolactones can by synthesized in the laboratory. Their therapeutic use in goiter has
been tested successfully. A possible application in proliferative mastopathy and breast cancer is conceivable
based on the associated pathophysiology.
Mastopathy, breast cancer and iodolactone [in German]
Torremante, P.
Dtsch Med Wochenschr. 2004 Mar 19;129(12):641-5.
TURKEN
Breast cancer in association with thyroid disorders.
Turken O, NarIn Y, DemIrbas S, Onde ME, Sayan O, KandemIr EG, YaylacI M, Ozturk A.
Breast Cancer Res. 2003;5(5):R110-3. Epub 2003 Jun 5.
BACKGROUND: The relationship between breast cancer and thyroid diseases is controversial. Discrepant
results have been reported in the literature. The incidences of autoimmune and nonautoimmune thyroid
diseases were investigated in patients with breast cancer and age-matched control individuals without breast or
thyroid disease.
METHODS: Clinical and ultrasound evaluation of thyroid gland, determination of serum thyroid hormone and
antibody levels, and fine-needle aspiration of thyroid gland were performed in 150 breast cancer patients and
100 control individuals.
RESULTS: The mean values for anti-thyroid peroxidase antibodies were significantly higher in breast cancer
patients than in control individuals (P = 0.030). The incidences of autoimmune and nonautoimmune thyroid
diseases were higher in breast cancer patients than in control individuals (38% versus 17%, P = 0.001; 26%
versus 9%, P = 0.001, respectively).
CONCLUSION: Our results indicate an increased prevalence of autoimmune and nonautoimmune thyroid
diseases in breast cancer patients.
UPADHYAY
Differential action of iodine on mitochondria from human tumoral- and extra-tumoral tissue in inducing the
release of apoptogenic proteins.
Upadhyay G, Singh R, Sharma R, Balapure AK, Godbole MM.
Mitochondrion. 2002 Dec;2(3):199-210.
"Iodide is actively concentrated in the thyroid gland for thyroid hormone biosynthesis. Excess iodine has been
observed to induce apoptosis in thyrocytes and mammary cells. The mechanism of iodine induced apoptosis is
poorly understood. Among various cell organelles, mitochondria is known to provide conducive environment for
the organification of iodine, i.e. iodination of different proteins. Mitochondria also play a central role in execution of
apoptosis. To study the role of mitochondria in iodine induced apoptosis, we investigated the direct interaction of
iodine and human breast mitochondria vis-a-vis its role in the initiation of apoptosis in vitro. We observed that
mitochondria isolated from the tumor (TT) and extra-tumoral tissue (ET) of human breast display significant
uptake of iodine. Mitochondrial proteins were observed to be predominantly iodinated in ET but not in TT
mitochondria. Treatment with iodine showed an increase in mitochondrial permeability transition of TT and
decrease in ET. Iodine induced released factor(s) other than cytochrome c from tumor mitochondria initiate(s)
apoptosis in vitro, while those from ET mitochondria were non-apoptogenic in nature. To our knowledge, this is
first report demonstrating that iodine acts differentially on mitochondria of tumor and extratumoral origin to
release apoptogenic proteins from TT and has a protective effect on ET."
Functional expression of sodium iodide symporter (NIS) in human breast cancer tissue.
Upadhyay G, Singh R, Agarwal G, Mishra SK, Pal L, Pradhan PK, Das BK, Godbole MM.
Breast Cancer Res Treat. 2003 Jan;77(2):157-65.
"Sodium iodide symporter (NIS) is a molecule involved in active accumulation of iodine in thyroid gland for the
biosynthesis of thyroid hormone. Its expression has also been demonstrated in extra-thyroidal tissues including
lactating mice mammary gland and also in human breast cancers. Iodide transport in thyroid cells through NIS is
the basis for using radioiodine for diagnosis and treatment of differentiated thyroid carcinoma. The similar
approach may prove beneficial for the diagnosis and treatment of breast cancer if iodine uptake, its retention and
NIS expression can be shown unequivocally in malignant tumors. The aim of the present study was to investigate
NIS expression, in vivo iodine transport ability and fate of iodine in human breast tumors. Women (age 33-58
years) with infiltrating duct carcinoma confirmed by FNAC and subsequent histopathology were the subject of this
study. Expression of NIS RNA and protein was confirmed by RNAase protection assay, western blot and
immunohistochemistry respectively in surgically excised breast tumor tissue. Iodine transport ability and its
nature was assessed both in vivo and in vitro. We report high NIS expression at both transcriptional and
translational level and its ability to transport iodine in human breast tumors. The in vivo iodine transport ability
was confirmed by scintigraphy. Unlike thyroid, perchlorate and thiocyanate do not inhibit iodine transport in breast
tumors. The presence of iodinated proteins suggests the longer retention time. The unequivocal demonstration
of NIS expression, its functionality and retention of iodine by organification further provides supportive evidence
for use of radioiodine as an additional treatment modality of human breast carcinoma."
VENTURI
Is there a role for iodine in breast diseases?
Venturi S., 2001.
Breast. 2001 Oct;10(5):379-82.
“It is hypothesized that dietary iodine deficiency is associated with the development of mammary pathology and
cancer. A review of the literature on this correlation and of the author's own work on the antioxidant function of
iodide in iodide-concentrating extrathyroidal cells is reported. Mammary gland is embryogenetically derived from
primitive iodide-concentrating ectoderm, and alveolar and ductular cells of the breast specialize in uptake and
secretion of iodine in milk in order to supply offspring with this important trace-element. Breast and thyroid share
an important iodide-concentrating ability and an efficient peroxidase activity, which transfers electrons from iodide
to the oxygen of hydrogen peroxide, forming iodoproteins and iodolipids, and so protects the cells from
peroxidative damage. The mammary gland has only a temporary ability to concentrate iodides, almost exclusively
during pregnancy and lactation, which are considered protective conditions against breast cancer.
Role of iodine in evolution and carcinogenesis of thyroid, breast and stomach.
Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A.
Adv Clin Path. 2000 Jan;4(1):11-7. Review.
The authors have hypothesized that dietary iodine (deficiency or excess) is associated with the development of
some gastric and mammary cancers, as it is well-known for thyroid cancer. They report a short review of their
own work and of the general literature on this correlation and on the antioxidant function of iodide in stomach,
breast and thyroid. Thyroid cells phylogenetically derived from primitive iodide-concentrating gastroenteric cells
which, during evolution, migrated and specialized in uptake and storage of iodine, also in order to adapt the
organisms from iodine-rich sea to iodine-deficient land. Mammary cells also derived from primitive iodide-
concentrating ectoderm. Stomach, breast and thyroid share an important iodide-concentrating ability and an
efficient peroxidase activity, which transfers electrons from iodides to the oxygen of hydrogen peroxide and so
protects the cells from damage caused by lipid peroxidation. The authors suggest that iodide might have an
ancestral antioxidant function in all iodide-concentrating cells from primitive Algae to more recent Vertebrates. In
Italy, gastric cancer is more frequent in farmers and in iodine-deficient populations, living in mountainous and
hilly areas, than in fishermen. In the last two decades, Italian decrease of gastric cancer seems to be correlated
more to the higher dietary consumption of iodine-rich fish rather than to consumption of fruit and vegetables,
which indeed has decreased in Italy.
Breast pg 5 (cont)
SARAIVA
Profile of thyroid hormones in breast cancer patients.
Saraiva PP, Figueiredo NB, Padovani CR, Brentani MM, Nogueira CR.
Braz J Med Biol Res. 2005 May;38(5):761-5. Epub 2005 May 25.
Estrogen involvement in breast cancer has been established; however, the association between breast cancer
and thyroid diseases is controversial. Estrogen-like effects of thyroid hormone on breast cancer cell growth in
culture have been reported. The objective of the present study was to determine the profile of thyroid hormones in
breast cancer patients.
Serum aliquots from 26 patients with breast cancer ranging in age from 30 to 85 years and age-matched normal
controls (N = 22) were analyzed for free triiodothyronine (T3F), free thyroxine (T4F), thyroid-stimulating hormone
(TSH), antiperoxidase antibody (TPO), and estradiol (E2). Estrogen receptor ss (ERss) was determined in tumor
tissues by immunohistochemistry.
Thyroid disease incidence was higher in patients than in controls (58 vs 18%, P < 0.05). Subclinical
hyperthyroidism was the most frequent disorder in patients (31%); hypothyroidism (8%) and positive anti-TPO
antibodies (19%) were also found. Subclinical hypothyroidism was the only dysfunction (18%) found in controls.
Hyperthyroidism was associated with postmenopausal patients, as shown by significantly higher mean T3 and
T4 values and lower TSH levels in this group of breast cancer patients than in controls. The majority of positive
ERss tumors were clustered in the postmenopausal patients and all cases presenting subclinical
hyperthyroidism in this subgroup concomitantly exhibited Erss-positive tumors. Subclinical hyperthyroidism was
present in only one of 6 premenopausal patients.
We show here that postmenopausal breast cancer patients have a significantly increased thyroid hormone/E2
ratio (P < 0.05), suggesting a possible tumor growth-promoting effect caused by this misbalance.
SEKIYA
Intracellular signaling in the induction of apoptosis in a human breast cancer cell line by water extract of Mekabu.
Sekiya M, Funahashi H, Tsukamura K, Imai T, Hayakawa A, Kiuchi T, Nakao A.
Int J Clin Oncol. 2005 Apr;10(2):122-6.
BACKGROUND: We previously reported that water extract of Mekabu, a kind of seaweed, induced apoptosis in a
human breast cancer cell line. In the present study we investigated intracellular signaling in apoptosis, with a
focus on caspases.
METHODS: Mekabu extract, obtained with ultrapure water, was used to induce apoptosis in a human breast
cancer cell line, MDA-MB231, and DNA fractionation was investigated by flow cytometry and electrophoresis. In
addition, using the caspase detection kit Caspa Tag, activation of caspases 3, 6, 8, and 9 was observed under a
fluorescence microscope. Furthermore, using antibodies to caspases 3, 8, 9, and Bid, we conducted a protein
analysis by Western blotting to determine the activation of these substances.
RESULTS: Obvious ladder formation demonstrating DNA fractionation was seen, confirming that Mekabu extract
induced apoptosis. In the fluorescence microscope observations, activation of caspases 3, 6, and 8, but not
caspase 9, was seen. Activated caspases 3 and 8 were detected in the Western blotting analysis, but no proteins
of activated caspase 9 or Bid were detected.
CONCLUSION: Mekabu extract activates caspases 3, 6, and 8 and contributes to intracellular signaling to induce
apoptosis in a human breast cancer cell line. This signaling is not via the mitochondria.
SHRIVASTAVA
Molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells involving
mitochondria-mediated pathway.
Shrivastava A, Tiwari M, Sinha RA, Kumar A, Balapure AK, Bajpai VK, Sharma R, Mitra K, Tandon A, Godbole MM
J Biol Chem. 2006 Jul 14;281(28):19762-71. Epub 2006 May 5.
Molecular iodine (I(2)) is known to inhibit the induction and promotion of N-methyl-n-nitrosourea-induced
mammary carcinogenesis, regresses 7, 12-Dimethylbenz (a)-anthracene-induced breast tumors in rat and has
also shown beneficial effect in the fibrocystic human breast disease. Cytotoxicity of iodine on cultured human
breast cancer cell lines viz. MCF-7, MDA-MB-231, MDA-MB-453, ZR-75-1 and T-47D is reported in this
communication. Iodine induces apoptosis in all the cell lines tested, except MDA-MB-231 shown by sub-G1 peak
analysis using flow cytometry. Iodine inhibited proliferation of normal human peripheral blood mononuclear cells,
however did not induce apoptosis in these cells. Iodine-induced apoptotic mechanism was studied in MCF-7
cells. DNA fragmentation analysis confirmed internucleosomal DNA degradation. Terminal deoxynucleotidyl
transferase-dUTP nick end labeling established that iodine induces apoptosis in time and dose- dependent
manner in MCF-7 cells. Iodine-induced apoptosis is independent of caspases. Iodine dissipates mitochondrial
membrane potential, exhibits an antioxidant activity and causes depletion in total cellular thiol content. Western
blot results showed decrease in Bcl-2 and upregulation of Bax. Immunofluorescence studies confirmed
activation and mitochondrial membrane localization of Bax. Ectopic Bcl-2 overexpression did not rescue iodine-
induced cell death. Iodine treatment induces translocation of Apoptosis inducing factor from mitochondria to the
nucleus. Treatment of N-acetyl-L-cysteine prior to iodine exposure restored basal thiol content, ROS levels and
completely inhibited nuclear translocation of Apoptosis inducing factor and subsequently cell death, indicating
that thiol depletion may play an important role in iodine-induced cell death. These results demonstrate that iodine
treatment activates a caspase-independent and mitochondria-mediated apoptotic pathway.
SKIBOLA
Brown kelp modulates endocrine hormones in female sprague-dawley rats and in human luteinized granulosa
cells.
Skibola CF, Curry JD, VandeVoort C, Conley A, Smith MT.
J Nutr. 2005 Feb;135(2):296-300.
Epidemiological studies suggest that populations consuming typical Asian diets have a lower incidence of
hormone-dependent cancers than populations consuming Western diets. These dietary differences have been
mainly attributed to higher soy intakes among Asians. However, studies from our laboratory suggest that the anti-
estrogenic effects of dietary kelp also may contribute to these reduced cancer rates. As a follow-up to previous
findings of endocrine modulation related to kelp ingestion in a pilot study of premenopausal women, we
investigated the endocrine modulating effects of kelp (Fucus vesiculosus) in female rats and human luteinized
granulosa cells (hLGC)…. These data show endocrine modulating effects of kelp at relevant doses and suggest
that dietary kelp may contribute to the lower incidence of hormone-dependent cancers among the Japanese.
The effect of Fucus vesiculosus, an edible brown seaweed, upon menstrual cycle length and hormonal status in
three pre-menopausal women: a case report.
Skibola CF.
BMC Complement Altern Med. 2004 Aug 4;4:10.
BACKGROUND: Rates of estrogen-dependent cancers are among the highest in Western countries and lower in
the East. These variations may be attributable to differences in dietary exposures such as higher seaweed
consumption among Asian populations. The edible brown kelp, Fucus vesiculosus (bladderwrack), as well as
other brown kelp species, lower plasma cholesterol levels. Since cholesterol is a precursor to sex hormone
biosynthesis, kelp consumption may alter circulating sex hormone levels and menstrual cycling patterns. In
particular, dietary kelp may be beneficial to women with or at high risk for estrogen-dependent diseases. To test
this, bladderwrack was administered to three pre-menopausal women with abnormal menstrual cycling patterns
and/or menstrual-related disease histories.
CASE PRESENTATION: Intake of bladderwrack was associated with significant increases in menstrual cycle
lengths, ranging from an increase of 5.5 to 14 days. In addition, hormone measurements ascertained for one
woman revealed significant anti-estrogenic and progestagenic effects following kelp administration. Mean
baseline 17beta-estradiol levels were reduced from 626 +/- 91 to 164 +/- 30 pg/ml (P = 0.04) following 700 mg/d,
which decreased further to 92.5.0 +/- 3.5pg/ml (P = 0.03) with the 1.4 g/d dose. Mean baseline progesterone
levels rose from 0.58 +/- 0.14 to 8.4 +/- 2.6 ng/ml with the 700 mg/d dose (P = 0.1), which increased further to
16.8 +/- 0.7 ng/ml with the 1.4 g/d dose (P = 0.002).
CONCLUSIONS: These pilot data suggest that dietary bladderwrack may prolong the length of the menstrual
cycle and exert anti-estrogenic effects in pre-menopausal women. Further, these studies also suggest that
seaweed may be another important dietary component apart from soy that is responsible for the reduced risk of
estrogen-related cancers observed in Japanese populations. However, these studies will need to be performed
in well-controlled clinical trials to confirm these preliminary findings.
SMYTH
Role of iodine in antioxidant defense in thyroid and breast disease.
Smyth PP.
Biofactors. 2003;19(3-4):121-30. Review.
The role played in thyroid hormonogenesis by iodide oxidation to iodine (organification) is well established.
Iodine deficiency may produce conditions of oxidative stress with high TSH producing a level of H2O2, which
because of lack of iodide is not being used to form thyroid hormones. The cytotoxic actions of excess iodide in
thyroid cells may depend on the formation of free radicals and can be attributed to both necrotic and apoptotic
mechanisms with necrosis predominating in goiter development and apoptosis during iodide induced involution.
These cytotoxic effects appear to depend on the status of antioxidative enzymes and may only be evident in
conditions of selenium deficiency where the activity of selenium containing antioxidative enzymes is impaired.
Less compelling evidence exists of a role for iodide as an antioxidant in the breast. However the Japanese
experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet.
Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is
breast specific and its possible relationship to iodine or selenium status awaits resolution.
Iodine can react with double bonds on lipids such as polyunsaturated fatty acids rendering them less reactive to
ROS. Polyunsaturated fatty acids such as arachidonic acid which is known to play a role in intracellular signalling
in the thyroid contains four double bonds and can be easily oxidised and thus contribute to increased lipid
peroxidation [32]. It has been postulated that formation of iodolipids such as iodolactones or iodoaldehydes
represents a form of thyroidal autoregulation [33] which may be the mode of action of iodide inhibition of thyroidal
function in the Wolff-Chaikoff effect [6,34,35]. While lower doses of iodide are necessary substrates for TPO
mediated conversion into I2, iodinated compounds (so called XI) at high doses may exert inhibitory effects on
adenylate-cyclase, NADPH-oxidase and TPO activities [6,35]. This effect seems to require oxidation of I− to I2 as
inhibitors of TPO or I− trapping can reverse the inhibitory effect [35].
A role for iodide as an antioxidant possibly through a protective action of iodolipids as described for the thyroid
has been suggested [64–66]. This is on the basis of a shared iodide concentrating mechanism in both thyroid
and breast as well as a requirement for an iodide oxidation system to provide for the formation of iodoamino
acids leading to thyroid hormone formation in the thyroid and to iodinated milk proteins by the breast necessary
for neonatal nutrition [50–52]. Figure 3 shows in cartoon form the uptake of I− by the breast and its incorporation
into iodoproteins. When taken into the breast I− is incorporated into lactoproteins presumably as a result of
organification into I2 by lactoperoxidases [57,66]. These iodoproteins together with free I− are secreted in breast
milk. As mentioned elsewhere in this communication, I− may also be incorporated into iodolipids such as
iodolactones or iodoaldehydes which in the thyroid have been shown to possess antiproliferative properties. To
date there is no evidence that a similar effect is produced in the breast.
The thyroid, iodine and breast cancer.
Smyth PP.
Breast Cancer Res. 2003;5(5):235-8. Epub 2003 Jul 29.
A renewal of the search for a link between breast cancer and thyroid disease has once again demonstrated an
increased prevalence of autoimmune thyroid disease in patients with breast cancer. This is the most recent of
many studies showing an association between a variety of thyroid disorders and breast cancer. Such an
association is not surprising as both diseases are female predominant with a similar postmenopausal peak
incidence. The significance of the presence of thyroid autoantibodies, particularly thyroid peroxidase antibodies,
in serum from patients with breast cancer is unknown, but it has been suggested that antibody positivity is
associated with better prognosis. One area in which thyroid and breast functions overlap is in the uptake and
utilization of dietary iodide. Experimental findings showing the ability of iodine or iodine-rich seaweed to inhibit
breast tumour development is supported by the relatively low rate of breast cancer in Japanese women who
consume a diet containing iodine-rich seaweed. However, there is as yet no direct evidence that iodine, iodinated
compounds, or a combination of iodine and selenium is the antimammary carcinogenic element in the
Japanese diet. It remains to be resolved whether the perceived breast cancer-thyroid disease relationship is
thyroid or iodine related or, in the case of thyroid autoantibodies, is the consequence of an immune response to
the carcinoma. Is this response breast specific and does it relate to iodine status? These and many other
questions await resolution before a definitive role in the natural history of breast carcinoma can be assigned to
the thyroid.
Tissue iodine content and serum-mediated 125I uptake-blocking activity in breast cancer.
Kilbane MT, Ajjan RA, Weetman AP, Dwyer R, McDermott EW, O'Higgins NJ, Smyth PP.J Clin Endocrinol Metab.
2000 Mar;85(3):1245-50.
In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in
the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2
of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total
tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher
than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal
tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I
uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49
(16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched
female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide
uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly
associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in
those with benign breast disease, once again suggesting an association between thyroid autoimmunity and
breast carcinoma.
Autoimmune thyroid disease and breast cancer: a chance association?
Smyth PP.
J Endocrinol Invest. 2000 Jan;23(1):42-3. Review.
[citation only]
Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma.
Smyth PP, Shering SG, Kilbane MT, Murray MJ, McDermott EW, Smith DF, O'Higgins NJ.
J Clin Endocrinol Metab. 1998 Aug;83(8):2711-6.
The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast
carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was
studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma,
compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease,
compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast
carcinoma demonstrated that TPO.Ab titres > or = 0.3 U/mL were associated with a significantly better disease-
free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were
TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid
volumes within the intermediate range (10.1-18.8 mL) and did not further enhance the good outcome recorded
when volumes were < or = 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and
thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free
survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status
or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a
beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a
biological link between breast carcinoma and thyroid disease.
The thyroid and breast cancer: a significant association?
Smyth PP.
Ann Med. 1997 Jun;29(3):189-91.
[abstract only]
The coincidence of thyroid disorders and breast cancer has long been a subject of debate. Associations with
hyperthyroidism, hypothyroidism, thyroiditis and nontoxic goitre have been reported. Although no convincing
evidence exists of a causal role for overt thyroid disease in breast cancer, the preponderance of published work
favours an association with hypothyroidism. Geographical variations in the incidence of breast cancer have been
attributed to differences in dietary iodine intake and an effect of iodide on the breast has been postulated. Recent
reports have shown a direct association between thyroid enlargement, as assessed by ultrasound, and breast
cancer. Although the exact mechanism for the demonstrated association between diseases of the thyroid and
breast cancer remains to be elucidated, there is at least the possibility that the presence of thyroid abnormalities
may influence breast cancer progression and this alone should stimulate awareness into the coincidence of the
two disorders.
A direct relationship between thyroid enlargement and breast cancer.
Smyth PP, Smith DF, McDermott EW, Murray MJ, Geraghty JG, O'Higgins NJ.
J Clin Endocrinol Metab. 1996 Mar;81(3):937-41.
[abstract only]
Despite extensive study, evidence to support a direct relationship between diseases of the thyroid and breast has
not been established. In this study thyroid volume was assessed by ultrasound in 200 patients with breast
cancer and 354 with benign breast disease. Results were compared to appropriate female control groups. Both
mean thyroid volume (21.1 +/- 1.4 mL) and the percentage of individual patients with enlarged (> 18.0 mL) thyroid
glands (41.5%) were significantly greater in the breast cancer group than equivalent values (13.2 +/- 0.5 mL and
10.5%, respectively) in age-matched controls (P < 0.01 in both cases). The mean thyroid volume of 14.5 +/- 0.34
mL in patients with benign breast disease was also significantly greater than that of 12.5 +/- 0.38 mL in younger
controls (P < 0.01). The results support a direct association between breast cancer and increased thyroid volume
as mean thyroid volumes and the percentage of individual patients with enlarged thyroid glands were similar in
those studied both before (20.8 +/- 1.3 mL and 43.0%) and after (21.4 +/- 1.6 mL and 40.0%) therapies for breast
cancer. Although there is no evidence that thyroid enlargement represents a risk factor for breast cancer, the
results emphasize the importance of raising the consciousness of the coincidence of both disorders.
SPITZWEG
Mammary radioiodine accumulation due to functional sodium iodide symporter expression in a benign
fibroadenoma.
Berger F, Unterholzner S, Diebold J, Knesewitsch P, Hahn K, Spitzweg C.
Biochem Biophys Res Commun. 2006 Nov 3;349(4):1258-63. Epub 2006 Sep 7.
[abstract only]
The sodium iodide symporter (NIS) has been characterized to mediate the active transport of iodide not only in
the thyroid gland but also in various non-thyroidal tissues, including lactating mammary gland and the majority of
breast cancers, thereby offering the possibility of diagnostic and therapeutic radioiodine application in breast
cancer. In this report, we present a 57-year-old patient with multifocal papillary thyroid carcinoma, who showed
focal radioiodine accumulation in a lesion in the right breast on a posttherapy (131)I scan following radioiodine
therapy. CT and MR-mammography showed a focal solid lesion in the right breast suggestive of a fibroadenoma,
which was confirmed by histological examination. Immunostaining of paraffin-embedded tumor tissue sections
using a human NIS antibody demonstrated NIS-specific immunoreactivity confined to epithelial cells of mammary
ducts. In conclusion, in a thyroid cancer patient we identified a benign fibroadenoma of the breast expressing
high levels of functionally active NIS protein as underlying cause of focal mammary radioiodine accumulation on
a posttherapy (131)I scan. These data show for the first time that functional NIS expression is not restricted to
lactating mammary gland and malignant breast tissue, but can also be detected in benign breast lesions, such
as fibroadenomata of the breast.
Dexamethasone stimulation of retinoic Acid-induced sodium iodide symporter expression and cytotoxicity of 131-I
in breast cancer cells.
Unterholzner S, Willhauck MJ, Cengic N, Schutz M, Goke B, Morris JC, Spitzweg C.
J Clin Endocrinol Metab. 2006 Jan;91(1):69-78. Epub 2005 Oct 18.
[abstract only]
CONTEXT: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as
lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-
positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which
might offer the potential to treat breast cancer with radioiodine.
OBJECTIVE: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS
expression and therapeutic efficacy of 131-I in MCF-7 cells.
DESIGN: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern
and Western blot analysis after incubation with Dex (10(-9) to 10(-7) m) in the presence of atRA (10(-6) m) as well
as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity
was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro
clonogenic assay.
RESULTS: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up
to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide
accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after
stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of
131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-
7 cells treated with Dex in the presence of atRA.
CONCLUSION: Treatment with Dex in the presence of atRA significantly increases functional NIS expression
levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7
breast cancer cells.
STRUM
Autoradiographic evidence of a loss of iodination within hormone-dependent GR mouse mammary tumors as
they progress to independence.
Strum JM.
Anat Rec. 1982 Dec;204(4):323-32.
[abstract only]
The purpose of this study was to determine by use of light- and electron-microscope autoradiography whether or
not iodination occurred in mammary tumors of female GR mice. Of the sixty tumors studied it was found that
pregnancy-dependent and hormone-induced tumors possessed iodinating ability. Although mammary glands
from nonpregnant GR mice lacked the ability to iodinate, by the 16th day of pregnancy in response to hormonal
stimulation the glands readily iodinated casein, and some epithelial cells contained ultrastructural cytochemical
evidence of mammary peroxidase. Preneoplastic mammary gland lesions known as hyperplastic alveolar
nodules were also able to iodinate, as were plaques, the disc-shaped lesions which give rise to the hormone-
responsive mammary tumors in this strain. Plaques also contained epithelial cells with mammary peroxidase
activity. When hormone-induced mammary tumors were transplanted into syngeneic mice they retained the ability
to iodinate for several generations. However, as the tumors progressed to hormone independence, the ability to
iodinate was gradually lost. Hormone-independent mammary tumors from GR mice lacked both iodinating ability
and cytochemical evidence of mammary peroxidase. These findings suggest that iodination depends upon
hormone-responsive cells within the mammary tumors and that as these cells become hormone unresponsive,
the ability to iodinate is lost.
Effect of iodide-deficiency on rat mammary gland.
Strum JM.
Virchows Arch B Cell Pathol Incl Mol Pathol. 1979 May 31;30(2):209-20.
When rats are kept iodide-deficient, atrophy and necrosis takes place in the mammary gland and areas of
dysplasia and atypia are seen. Administration of estradiol to iodide-deficient rats stimulates cell division in the
gland and leads to the formation of alveoli. Continued stimulation by estradiol produces changes in the newly-
formed alveolar cells. Their nucleoli are altered and show a separation of components. Ribosomes and lipid
droplets increase and the cells synthesize large vacuoles containing protein. The secretion of great quantities of
this material into areas of the tissue where regressive changes have occurred undoubtedly contributes to the
formation of cysts within the gland. The present findings indicate that iodide-deficiency alters the structure and
function of mammary gland alveolar cells and makes them highly sensitive to stimulation by estradiol.
Site of iodination in rat mammary gland.
Strum JM.
Anat Rec. 1978 Oct;192(2):235-44.
The ability of the mammary gland to take up and organically bind radioiodide was studied in non-pregnant,
pregnant, and lactating rats. Autoradiography was used to determine whether duct cells or alveolar cells are
responsible for iodination in the rat mammary gland. Iodination was not detected in mammary glands from non-
pregnant rats, but occurred late in the twelfth day of gestation and continued throughout pregnancy and lactation.
Protein-containing vacuoles in alveolar cells and casein-like proteins in milk were the major sites where
iodination occurred within the gland. Milk proteins in the lumens of ductules adjacent to alveoli were also
iodinated. In contrast, ducts, myoepithelial cells, fat cells, blood vessels and other histological components of the
gland did not show iodinating capability. Cytochemistry was also used to identify endogenous mammary
peroxidase activity in the same glands, and it was found that the presence and location of this enzyme was
correlated with the ability to iodinate.
TAZEBAY
Unliganded estrogen receptor-alpha activates transcription of the mammary gland Na+/I- symporter gene.
Alotaibi H, Yaman EC, Demirpence E, Tazebay UH.
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1487-96. Epub 2006 May 15.
The function of sodium iodide symporter (Na(+)/I(-) symporter, or NIS) in mammary epithelial cells is essential for
the accumulation of I(-) in milk; the newborn's first source of I(-) for thyroid hormone synthesis. Furthermore,
increased mammary gland NIS expression has previously been shown in human breast cancer. Several
hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using
breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-
alpha (ERalpha) positive cells and we investigated the role of ERalpha in the regulation of NIS expression. We
showed that the suppression of endogenous ERalpha by RNA interference downregulates NIS expression in
ERalpha positive mammary cells. Besides, in an ERalpha negative cell line, reintroduction of ERalpha resulted
in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive
element in the promoter region of NIS that specifically binds ERalpha and mediates ERalpha-dependent
activation of transcription. Our results indicate that unliganded ERalpha (apo-ERalpha) contributes to the
regulation of NIS gene expression.
The mammary gland iodide transporter is expressed during lactation and in breast cancer.
Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG,
Carrasco N.
Nat Med. 2000 Aug;6(8):871-8.
The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By
exploiting this activity, radioiodide has been used for decades with considerable success in the detection and
treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the
mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland
and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland
sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice
bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of
the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared
with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the
mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide
should be studied as a possible option in the diagnosis and treatment of breast cancer.
Besides the thyroid, active iodide transport occurs in the lactating mammary gland, salivary glands and gastric
mucosa. Iodide concentrated in lactating mammary gland and secreted into milk is used by the nursing newborn
for the biosynthesis of thyroid hormones.... The mammary gland iodide transporter was the essential link in the
chain of events that led to a higher thyroid cancer incidence in the aftermath of the Chernobyl power plant
accident. I-131 in radioactive fallout was accumulated by cattle in milk, and children who ingested I-131
contaminated milk subsequently concentrated I-131 in their thyroids through the thyroid NIS, exposing the gland
to tumorigenic doses of radiation.
Effects of hormones on mgNIS [mammary gland NIS] expression in ovariectomized mice. We administered 17-B-
estradiol, progesterone, oxytocin, and prolactin, both individually and in different combinations, to nubile
ovariectomized adult mice and assessed mgNIS expression in mammary tissue. Administration of oxytocin
alone to ovariectomized mice did not cause an increase in mgNIS expression.... Of all the hormones tested
individually, only 17-B-estradiol led to a clearly discernible increase in mgNIS expression.... The upregulating
effect of oxytocin on mgNIS expression may require estrogen.
The greatest increase in mgNIS expression occurred after administration of 17-B-estradiol, oxytocin and prolactin
together.... When progesterone was added to the 17-B-estradiol-oxytocin-prolactin combination, mgNIS
expression was substantially decreased. Conversely, a comparison of mgNIS expression in mice treated with
estrogen or estrogen plus progesterone showed that progesterone did not interfere with 17-B-estradiol
enhancement of mgNIS expression. In conclusion, the combination of estrogen, prolactin and oxytocin (in the
absence of progesterone) led to the highest levels of mgNIS expression in ovariectomized mice. This
combination of hormones closely resembles the relative hormonal levels in mice and rats during lactation.
More than 80% of the breast cancer specimens analyzed expressed mgNIS, in contrast to no expression in
normal tissues from reductive mammoplasties, indicating that mgNIS is unregulated with a high frequency
during malignant transformation in human breast.
A threshold level of circulating estrogens seemed to be necessary for optimal mgNIS expression overall, and in
particular for the upregulation of mgNIS by oxytocin. The cooperative function of estrogens in the effect of oxytocin
on mgNIS may be explained by the likelihood that oxytocin receptor mRNA is upregulated by estrogen in the
breast, as it is in the hypothalamus and uterus. Additionally, estrogen may have a direct effect on mgNIS
transcription, as the NIS promoter contains several half-site estrogen-responsive elements.
In intact, nongestational, nonlactating animals, exogenous prolactin would cause endogenous estrogen levels,
which are lower than those in gestational or lactating animals, to decrease below the threshold, preventing
concomitantly administered oxytocin from stimulating mgNIS expression.... In the presence of high levels of
estrogen, prolactin may have a separate direct or indirect stimulatory effect on mgNIS expression by an as yet
unknown mechanism.... During lactation, estrogens would remain above the necessary threshold for oxytocin to
stimulate mgNIS expression and for prolactin to enhance, rather than antagonize, this effect.... The ability of
progesterone to inhibit the combined stimulatory effect of 17-B-Estradiol, oxytocin and prolactin on mgNIS
expression may involve a direct inhibition of oxytocin receptor signaling by competitive binding of progesterone to
the oxytocin receptor in the breast, similar to progesterone's effect in the uterus.
mgNIS expression may also be induced by nonhormonal factors involved in the malignant transformation of
mammary epithelial cells.
TEAS
Breast cancer disparities in South Carolina: early detection, special programs, and descriptive epidemiology.
Adams SA, Hebert JR, Bolick-Aldrich S, Daguise VG, Mosley CM, Modayil MV, Berger SH, Teas J, Mitas M,
Cunningham JE, Steck SE, Burch J, Butler WM, Horner MJ, Brandt HM.
J S C Med Assoc. 2006 Aug;102(7):231-9. Review.
A discrepancy exists between mortality and incidence rates between African-American and European-American
women in South Carolina. The relationship between tumor grade and the estrogen/ progesterone receptor status
is different in African-American and European-American women. African-American women with breast cancer
should be encouraged to participate in clinical trials, with the goal of identifying biological factors that might
facilitate the detection of tumors at an earlier stage and the development of more effective therapies. The most
important of our goals is to design studies to reduce the incidence of the disease and interventions to improve
survival and quality of life. The importance of participation in research cannot be overstated. Reproductive factors
such as early pregnancy and multiple pregnancies are strongly related to breast cancer risk, however, promotion
of these factors as a "prevention strategy," clearly does not lead to cogent, comprehensive public health
messages. Data from ecological and migrant studies point clearly to other factors that may be important such as
diet. Additional research around primary prevention strategies is needed. In addition, yearly mammograms
(secondary prevention) are recommended for women over 50 years old or those with relatives who have
developed breast cancer. The Best Chance Network, as a provider of screenings to low-income, uninsured
women, has helped to narrow the racial gap in screening that otherwise might exist (see Figures 3 and 4) to a
large extent. The determination for timing of surgery after diagnosis needs additional consideration. For example,
factors such as effective screening in younger women, timing of screening and surgery in relationship to the
ovulatory cycle, and season of screening and surgery may have a great impact on outcomes and may offer some
insight into the process of carcinogenesis and therapeutic efficacy. Research into this area is so novel that the
impact on possible ethnic disparities is completely unknown. The South Carolina Cancer Disparities Community
Network (SCCDCN) has identified the following areas as potential research foci: Identification of small media
interventions as an effective strategy to motivate targeted populations, especially those least likely to seek
screening for breast cancer and those least likely to participate in research programs (African-Americans).
Utilization of breast cancer survivors, self-identified as community natural helpers, can share their experiences
with their church congregation. A replication of such a program in South Carolina has great potential because of
the strong presence of the church, especially in rural parts of the state. Programs that closely integrate religion
with screening women for breast cancer are promising in this state. Development of a mammography registry
whereby information on all mammography procedures would be collected within a single database system
(much like a central cancer registry). This would aid in identifying population groups that could be targeted for
special programs and in the examination and exploration of the most appropriate modalities of detection. Such a
resource could also be a useful tool to encourage screening. Thus, this focus area has the potential to benefit
epidemiologic and health promotion research on many different levels. Additional breast cancer screening
methods should not be overlooked as a potential research focus. Mammography is not the only valid screening
method for breast cancer. Magnetic resonance imaging has shown some promise for screening among women
with a genetic predisposition for cancer. Another promising avenue is thermography. Because detection rates
may depend on age, ethnicity, and breast mammographic characteristics, women for whom regular screening
methods do not detect their cancers (e.g. older age, African-American ethnicity, dense breasts) must be identified
and other screening methods promoted within these populations. The above-mentioned mammography registry
would support this type of research.
The macrobiotic diet in cancer.
Kushi LH, Cunningham JE, Hebert JR, Lerman RH, Bandera EV, Teas J.
J Nutr. 2001 Nov;131(11 Suppl):3056S-64S. Review.
Macrobiotics is one of the most popular alternative or complementary comprehensive lifestyle approaches to
cancer. The centerpiece of macrobiotics is a predominantly vegetarian, whole-foods diet that has gained
popularity because of remarkable case reports of individuals who attributed recoveries from cancers with poor
prognoses to macrobiotics and the substantial evidence that the many dietary factors recommended by
macrobiotics are associated with decreased cancer risk. Women consuming macrobiotic diets have modestly
lower circulating estrogen levels, suggesting a lower risk of breast cancer. This may be due in part to the high
phytoestrogen content of the macrobiotic diet. As with most aspects of diet in cancer therapy, there has been
limited research evaluating the effectiveness of the macrobiotic diet in alleviating suffering or prolonging survival
of cancer patients. The few studies have compared the experience of cancer patients who tried macrobiotics with
expected survival rates or assembled series of cases that may justify more rigorous research. On the basis of
available evidence and its similarity to dietary recommendations for chronic disease prevention, the macrobiotic
diet probably carries a reduced cancer risk. However, at present, the empirical scientific basis for or against
recommendations for use of macrobiotics for cancer therapy is limited. Any such recommendations are likely to
reflect biases of the recommender. Because of its popularity and the compelling evidence that dietary factors are
important in cancer etiology and survival, further research to clarify whether the macrobiotic diet or similar dietary
patterns are effective in cancer prevention and treatment is warranted.
Dietary seaweed (Laminaria) and mammary carcinogenesis in rats.
Teas J, Harbison ML, Gelman RS.
Cancer Res. 1984 Jul;44(7):2758-61.
[abstract only]
To test the potential in vivo antitumor effect of dietary seaweed, we induced mammary tumors in female Sprague-
Dawley rats with the carcinogen 7,12-dimethylbenz(a)anthracene. Twenty-one-day-old rats (n = 108) were divided
into two groups. Controls were fed a standard semipurified diet, and experimental rats received the control diet
with 5% Laminaria, a brown seaweed, replacing 5% alphacel . At 55 days of age, each rat received 5 mg 7,12-
dimethylbenz(a)anthracene intragastrically. Rats were palpated for mammary tumors and weighed weekly for 26
weeks. Complete autopsies were then done on all rats. The seaweed diet did not alter weight gain or weights of
body organs at autopsy. Experimental rats had a significant delay in the time to tumor (p = 0.007); median time
until tumor was 19 weeks in experimental rats and 11 weeks in control animals. Among mammary
adenocarcinoma tumor-bearing animals, experimental rats had fewer adenocarcinomas/individual (p less than
0.05). There was also an overall 13% reduction in the number of experimental rats with histologically confirmed
adenocarcinomas (76% among the control rats compared to 63% among the experimental rats). Components of
Laminaria which might account for the observed difference in mammary tumor growth are varied and include the
sulfated polysaccharide fucoidan . Rats in the top row of cages had a significant (p = 0.01) delay in time to tumor
compared to rats in the lower four rows. In each row, the seaweed-fed rats had a longer time to tumor than did
the control rats.
The dietary intake of Laminaria, a brown seaweed, and breast cancer prevention.
Teas J
Nutr Cancer. 1983;4(3):217-22. Review.
[abstract only]
Based on epidemiological and biological data, Laminaria, a brown kelp seaweed, is proposed as an important
factor contributing to the relatively low breast cancer rates reported in Japan. Several possible mechanisms for
the influence of Laminaria on breast cancer are proposed: Laminaria is a source of nondigestible fiber, thereby
increasing fecal bulk and decreasing bowel transit time; it changes the posthepatic metabolism of sterols; it
contains an antibiotic substance that may influence fecal ecology; it contains 1-3 beta glucan, which alters
enzymatic activity of fecal flora; and it stimulates the host-mediated immune response. It is suggested that
Laminaria may play a role in preventing either the initiation of breast cancer or its promotion by endogenous
physiological factors.
The consumption of seaweed as a protective factor in the etiology of breast cancer.
Teas, J
Med Hypotheses. 1981 May;7(5):601-13.
A review of the biological properties of seaweed is presented and the role of seaweed as a breast cancer
anticarcinogen is suggested. Proposed mechanisms of action are: reduction of plasma cholesterol, binding of
biliary steroids, inhibition of carcinogenic fecal flora, binding of pollutants, stimulation of the immune system, and
the protective effects of beta-sitosterols. In an experiment using sarcoma-180 in mice, seaweed extract appeared
to have an antitumor effect. Thus it is suggested that breast cancer may be prevented and that this dietary habit
among the Japanese could be an important factor in understanding the lower breast cancer rates reported in
Japan.
TORREMANTE
Mastopathy, breast cancer and iodolactone [English Translation]
Torremante, P.
Dtsch Med Wochenschr. 2004 Mar 19;129(12):641-5.
Conclusion: A source of nutrition which emphasizes seafood and, thereby, provides a source of polyunsaturated
fatty acids and iodine is a dietary basis for iodolactone formation. This could be the reason for the low incidence
of breast cancer in Japan. Iodolactones can by synthesized in the laboratory. Their therapeutic use in goiter has
been tested successfully. A possible application in proliferative mastopathy and breast cancer is conceivable
based on the associated pathophysiology.
Mastopathy, breast cancer and iodolactone [in German]
Torremante, P.
Dtsch Med Wochenschr. 2004 Mar 19;129(12):641-5.
TURKEN
Breast cancer in association with thyroid disorders.
Turken O, NarIn Y, DemIrbas S, Onde ME, Sayan O, KandemIr EG, YaylacI M, Ozturk A.
Breast Cancer Res. 2003;5(5):R110-3. Epub 2003 Jun 5.
BACKGROUND: The relationship between breast cancer and thyroid diseases is controversial. Discrepant
results have been reported in the literature. The incidences of autoimmune and nonautoimmune thyroid
diseases were investigated in patients with breast cancer and age-matched control individuals without breast or
thyroid disease.
METHODS: Clinical and ultrasound evaluation of thyroid gland, determination of serum thyroid hormone and
antibody levels, and fine-needle aspiration of thyroid gland were performed in 150 breast cancer patients and
100 control individuals.
RESULTS: The mean values for anti-thyroid peroxidase antibodies were significantly higher in breast cancer
patients than in control individuals (P = 0.030). The incidences of autoimmune and nonautoimmune thyroid
diseases were higher in breast cancer patients than in control individuals (38% versus 17%, P = 0.001; 26%
versus 9%, P = 0.001, respectively).
CONCLUSION: Our results indicate an increased prevalence of autoimmune and nonautoimmune thyroid
diseases in breast cancer patients.
UPADHYAY
Differential action of iodine on mitochondria from human tumoral- and extra-tumoral tissue in inducing the
release of apoptogenic proteins.
Upadhyay G, Singh R, Sharma R, Balapure AK, Godbole MM.
Mitochondrion. 2002 Dec;2(3):199-210.
"Iodide is actively concentrated in the thyroid gland for thyroid hormone biosynthesis. Excess iodine has been
observed to induce apoptosis in thyrocytes and mammary cells. The mechanism of iodine induced apoptosis is
poorly understood. Among various cell organelles, mitochondria is known to provide conducive environment for
the organification of iodine, i.e. iodination of different proteins. Mitochondria also play a central role in execution of
apoptosis. To study the role of mitochondria in iodine induced apoptosis, we investigated the direct interaction of
iodine and human breast mitochondria vis-a-vis its role in the initiation of apoptosis in vitro. We observed that
mitochondria isolated from the tumor (TT) and extra-tumoral tissue (ET) of human breast display significant
uptake of iodine. Mitochondrial proteins were observed to be predominantly iodinated in ET but not in TT
mitochondria. Treatment with iodine showed an increase in mitochondrial permeability transition of TT and
decrease in ET. Iodine induced released factor(s) other than cytochrome c from tumor mitochondria initiate(s)
apoptosis in vitro, while those from ET mitochondria were non-apoptogenic in nature. To our knowledge, this is
first report demonstrating that iodine acts differentially on mitochondria of tumor and extratumoral origin to
release apoptogenic proteins from TT and has a protective effect on ET."
Functional expression of sodium iodide symporter (NIS) in human breast cancer tissue.
Upadhyay G, Singh R, Agarwal G, Mishra SK, Pal L, Pradhan PK, Das BK, Godbole MM.
Breast Cancer Res Treat. 2003 Jan;77(2):157-65.
"Sodium iodide symporter (NIS) is a molecule involved in active accumulation of iodine in thyroid gland for the
biosynthesis of thyroid hormone. Its expression has also been demonstrated in extra-thyroidal tissues including
lactating mice mammary gland and also in human breast cancers. Iodide transport in thyroid cells through NIS is
the basis for using radioiodine for diagnosis and treatment of differentiated thyroid carcinoma. The similar
approach may prove beneficial for the diagnosis and treatment of breast cancer if iodine uptake, its retention and
NIS expression can be shown unequivocally in malignant tumors. The aim of the present study was to investigate
NIS expression, in vivo iodine transport ability and fate of iodine in human breast tumors. Women (age 33-58
years) with infiltrating duct carcinoma confirmed by FNAC and subsequent histopathology were the subject of this
study. Expression of NIS RNA and protein was confirmed by RNAase protection assay, western blot and
immunohistochemistry respectively in surgically excised breast tumor tissue. Iodine transport ability and its
nature was assessed both in vivo and in vitro. We report high NIS expression at both transcriptional and
translational level and its ability to transport iodine in human breast tumors. The in vivo iodine transport ability
was confirmed by scintigraphy. Unlike thyroid, perchlorate and thiocyanate do not inhibit iodine transport in breast
tumors. The presence of iodinated proteins suggests the longer retention time. The unequivocal demonstration
of NIS expression, its functionality and retention of iodine by organification further provides supportive evidence
for use of radioiodine as an additional treatment modality of human breast carcinoma."
VENTURI
Is there a role for iodine in breast diseases?
Venturi S., 2001.
Breast. 2001 Oct;10(5):379-82.
“It is hypothesized that dietary iodine deficiency is associated with the development of mammary pathology and
cancer. A review of the literature on this correlation and of the author's own work on the antioxidant function of
iodide in iodide-concentrating extrathyroidal cells is reported. Mammary gland is embryogenetically derived from
primitive iodide-concentrating ectoderm, and alveolar and ductular cells of the breast specialize in uptake and
secretion of iodine in milk in order to supply offspring with this important trace-element. Breast and thyroid share
an important iodide-concentrating ability and an efficient peroxidase activity, which transfers electrons from iodide
to the oxygen of hydrogen peroxide, forming iodoproteins and iodolipids, and so protects the cells from
peroxidative damage. The mammary gland has only a temporary ability to concentrate iodides, almost exclusively
during pregnancy and lactation, which are considered protective conditions against breast cancer.
Role of iodine in evolution and carcinogenesis of thyroid, breast and stomach.
Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A.
Adv Clin Path. 2000 Jan;4(1):11-7. Review.
The authors have hypothesized that dietary iodine (deficiency or excess) is associated with the development of
some gastric and mammary cancers, as it is well-known for thyroid cancer. They report a short review of their
own work and of the general literature on this correlation and on the antioxidant function of iodide in stomach,
breast and thyroid. Thyroid cells phylogenetically derived from primitive iodide-concentrating gastroenteric cells
which, during evolution, migrated and specialized in uptake and storage of iodine, also in order to adapt the
organisms from iodine-rich sea to iodine-deficient land. Mammary cells also derived from primitive iodide-
concentrating ectoderm. Stomach, breast and thyroid share an important iodide-concentrating ability and an
efficient peroxidase activity, which transfers electrons from iodides to the oxygen of hydrogen peroxide and so
protects the cells from damage caused by lipid peroxidation. The authors suggest that iodide might have an
ancestral antioxidant function in all iodide-concentrating cells from primitive Algae to more recent Vertebrates. In
Italy, gastric cancer is more frequent in farmers and in iodine-deficient populations, living in mountainous and
hilly areas, than in fishermen. In the last two decades, Italian decrease of gastric cancer seems to be correlated
more to the higher dietary consumption of iodine-rich fish rather than to consumption of fruit and vegetables,
which indeed has decreased in Italy.
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The Iodine Movement
Iodine Supplementation
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Where to get Iodine
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