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The Seaweed Gatherers, Paul Gaugin
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Iodine Research
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Iodine and the Body
Breast pg 4 (cont)
FLECHAS
Breast Health: Iodine and Other Nutrients Play a Crucial Role
Flechas JD
Back in the early 1990s it was noted that patients who had iodine deficiency had associated benign breast changes.
By giving these patient’s iodine the breast changes that were present would regress. It had been noticed a few years
earlier that in animal studies, where the animal had been denied access to iodine, the animals developed benign
breast changes like humans.In animal studies, researchers have been able to produce breast cancer in animals by
depriving them of iodine.
"In my own personal medical practice I have literally seen the regression of cysts, nodules, scar tissue, and painful
breast with the use of 50 mg of Iodoral® per day for 2-3 years. The breast pain goes away in just a few weeks, but the
cyst/cysts, scar tissue and breast nodules take up to 2 to 3 years to resolve. On mammograms I have seen a 50 to 80
percent reduction in the scar tissue present in the breast. Studies are needed to show via biopsy that the many
different types of FBD will regress with iodine supplementation.
"Before starting on iodine therapy, a patient should have their thyroid hormone values investigated. A doctor should
check the size of the thyroid for enlargement and or nodules. An iodine-loading test should also be done prior to
starting iodine therapy to establish the need for iodine therapy. In this test the patient is given 50 mg of iodine and a
24-hour urine test is then collected. The iodine level in the urine is measured. The more saturated the body is with
iodine the higher the level of iodine excreted. The more saturated the body is, the less breast abnormalities have
been seen. The test is repeated at 3 months to document increasing saturation. If saturation is not occurring then
further investigation is called for to find out why saturation isn’t happening.
FUNAHASHI
Seaweed prevents breast cancer?
Funahashi H, Imai T, Mase T, Sekiya M, Yokoi K, Hayashi H, Shibata A, Hayashi T, Nishikawa M, Suda N, Hibi Y,
Mizuno Y, Tsukamura K, Hayakawa A, Tanuma S.,
Jpn J Cancer Res. 2001 May;92(5):483-7.
To investigate the chemopreventive effects of seaweed on breast cancer, we have been studying the relationship
between iodine and breast cancer. We found earlier that the seaweed, wakame, showed a suppressive effect on the
proliferation of DMBA (dimethylbenz(a)anthracene)-induced rat mammary tumors, possibly via apoptosis induction. In
the present study, powdered mekabu was placed in distilled water, and left to stand for 24 h at 4 degrees C. The
filtered supernatant was used as mekabu solution. It showed an extremely strong suppressive effect on rat
mammary carcinogenesis when used in daily drinking water, without toxicity. In vitro, mekabu solution strongly
induced apoptosis in 3 kinds of human breast cancer cells. These effects were stronger than those of a
chemotherapeutic agent widely used to treat human breast cancer. Furthermore, no apoptosis induction was
observed in normal human mammary cells. In Japan, mekabu is widely consumed as a safe, inexpensive food. Our
results suggest that mekabu has potential for chemoprevention of human breast cancer.
Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in
rats
Funahashi H, Imai T, Tanaka Y, Tsukamura K, Hayakawa Y, Kikumori T, Mase T, Itoh T, Nishikawa M, Hayashi H,
Shibata A, Hibi Y, Takahashi M, Narita T.
Jpn J Cancer Res. 1999 Sep;90(9):922-7.
We examined the anti-tumor proliferation effects of wakame seaweed on 7,12-dimethylbenz(a)-anthracene (DMBA)-
induced rat mammary tumor….Significant suppression of tumor growth was observed in groups I-B and I-C
compared with I-A. In groups I-B and I-C, the weights of resected mammary tumors were significantly lower and
serum total iodine concentration was significantly higher than in I-A. BrdU indices were significantly lower in groups I-
B and I-C, compared with I-A. TGF-beta and apoptotic index were inversely related to BrdU. These results suggest
that iodine is transported from the serum into mammary tissues and induces apoptosis through the expression of
TGF-beta. In conclusion, wakame suppressed the proliferation of DMBA-induced mammary tumors.
Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat.
Funahashi H, Imai T, Tanaka Y, Tobinaga J, Wada M, Morita T, Yamada F, Tsukamura K, Oiwa M, Kikumori T, Narita
T, Takagi H.,
J Surg Oncol. 1996 Mar;61(3):209-13.
Concerning the suppressive effect of inorganic iodine on the growth of 7,12-dimethyl-benz(a)anthracene (DMBA)-
induced breast tumor in female Sprague-Dawley (SD) rats, we previously reported that although iodine itself had a
suppressive effect on the tumor growth, its effect was not as strong as that of MPA (medroxy-progesterone acetate).
However, the combined medication of iodine at a low concentration + MPA showed a stronger effect than MPA alone.
The purpose of the present study is to elucidate this mechanism of action by determining the uptake of the
administered iodine into breast tumor tissue. Breast tumors were induced with DMBA in female SD rats, and these
animals were treated with MPA + inorganic iodine at various concentrations for 4 weeks to determine tumor growth
and tumor iodine content. In the comparison of tissue iodine content in growth-suppressive tumors with that in
nonsuppressive tumors, the former showed a much higher iodine content. This suggests that direct uptake of
inorganic iodine by breast tumors led to the suppression of tumor growth.
GARCIA-SOLIS
Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by molecular iodine (I2) but not by iodide (I-)
treatment Evidence that I2 prevents cancer promotion.
Garcia-Solis P, Alfaro Y, Anguiano B, Delgado G, Guzman RC, Nandi S, Diaz-Munoz M, Vazquez-Martinez O, Aceves C.
Mol Cell Endocrinol. 2005 May 31;236(1-2):49-57. Epub 2005 Apr 13.
We analyzed the effect of molecular iodine (I2), potassium iodide (KI) and a subclinical concentration of thyroxine (T4)
on the induction and promotion of mammary cancer induced by N-methyl-N-nitrosourea. Virgin Sprague-Dawley rats
received short or continuous treatment. Continuous I2 treated rats exhibited a strong and persistent reduction in
mammary cancer incidence (30%) compared to controls (72.7%). Interruption of short or long term treatments
resulted in a higher incidence in mammary cancer compared to the control groups. The protective effect of I2 was
correlated with the highest expression of the I-/Cl- transporter pendrin and with the lowest levels of lipoperoxidation
expression in mammary glands. Triiodothyronine serum levels and Na+/I- symporter, lactoperoxidase, or p53
expression did not show any changes. In conclusion continuous I2 treatment has a potent antineoplastic effect on the
progression of mammary cancer and its effect may be related to a decrease in the oxidative cell environment.
Differential uptake and signaling or molecular iodine (I2) in lactating, virgin, or neoplastic mammary glands
Garcia-Solis P, Delgado G, Anguiano B, Aceves C
13th International Thyroid Meeting, Buenos Aires, Arg. (Abstract) Thyroid 15 (Suppl 1) S-128.
[abstract only]
Conclusion: 1) I2 is differentially taken up by lactating, virgin and neoplastic MG [mammary gland], suggesting the
existence of mammary iodine uptake pathways in addition to NIS and PEN. 2) Gene expression of thyroid and MG is
differentially regulated by I2.
5'Deiodinase in two breast cancer cell lines: effect of triiodothyronine, isoproterenol and retinoids.
Garcia-Solis P, Aceves C.
Mol Cell Endocrinol. 2003 Mar 28;201(1-2):25-31.
Abstract only
Thyroid hormones participate in the regulation of growth, development and energy expenditure of vertebrates. Type I
(D1) and type II 5'deiodinases catalyze the peripheral conversion of the thyroid prohormone thyroxine to the active
form triiodothyronine (T3). D1 is expressed in organs like liver, thyroid, and lactating mammary gland. This enzyme is
regulated in an organ-specific manner by a wide number of factors like carbohydrates, T3, thyrotropin, and
catecholamines. However, it has been shown that in several types of cancer the expression of D1 is reduced, lost, or
regulated by different components. In the present work we describe the expression and regulation of 5'deiodinases
in two breast cancer cell lines: MCF-7 (ovarian hormone-dependent) and MDA-MB-231 (ovarian hormone-
independent). Our results showed that MCF-7 cells expressed D1 activity ( approximately 10 pmol I(-)/mg protein per
h), which was stimulated only by retinoic acid treatments, but not by T3 or the beta-adrenergic agonist isoproterenol.
In MDA-MB-231 cells, deiodinase activity was not detected in control conditions nor under any of these treatments.
These results support the notion that D1 expression could represent a sensitive differentiation marker.
GIANI
Thyroid autoimmunity in patients with malignant and benign breast diseases before surgery.
Giustarini E, Pinchera A, Fierabracci P, Roncella M, Fustaino L, Mammoli C, Giani C.
Eur J Endocrinol. 2006 May;154(5):645-9.
[abstract only]
BACKGROUND: Previous studies have demonstrated a high prevalence of thyroperoxidase antibodies (TPOAb)
and autoimmune hypothyroidism in breast cancer (BC). These studies have been performed in BC patients
generally 20-30 days after mastectomy. It is known that stress may have an influence on the immune system and
a relation between stressful events and the onset or worsening of autoimmune thyroid disorders has been
reported by several authors. The aim of the study was to evaluate the prevalence of autoimmune thyroid disease
in patients with nodular breast disease selected for surgery before any treatment. Our hypothesis was that the
high prevalence of thyroid autoimmune disorders in BC is independent of stressful events represented by
surgery and/or anaesthetic procedures.
METHODS: Our series included 61 consecutive women aged 52.8 +/- 10.2 yrs (mean age +/- s.d.) with nodular
breast disease selected for breast surgery: 36 out of 61 of them (59%) had BC and 25 out of 61 had benign breast
disease (BBD). Controls included 100 healthy age-matched women. All patients and control subjects were
submitted to clinical, ultrasound thyroid evaluation and serum-free thyroxine (FT4), serum-free tri-iodothyronine
(FT3), TSH, TPOAb and thyroglobulin antibodies (TgAb) determination.
RESULTS: Mean FT3, FT4 and TSH concentration showed no differences between BC patients, BBD patients and
controls. The prevalence of TPOAb in BC patients (12/36: 33.33%) was significantly higher than in BBD patients
(5/25: 20%) (P < 0.01) and in controls (8/100: 8%) (P < 0.01). Similarly, the prevalence of TgAb in BC patients was
12 out of 36 (33.33%) significantly higher than that detected in BBD patients (4/25: 16%) (P < 0.01) and in controls
(12/100: 12%) (P < 0.01). Of the 36 BC patients, 20 showed a diffuse hypoechogenicity of the thyroid gland to
ultrasound evaluation, significantly higher than in BBD (7/25: 28%) (P = 0.03). Of the 20 BC patients who showed a
hypoechogenic pattern of thyroid gland, 10 (50%) were associated with antithyroid antibodies positivity (TAb).
This finding was present in two of seven BBD (28.57%) (P < 0.0001). Only two controls showed focal
hypoechogenicity of the thyroid gland. Generally, 24 out of 36 (66.7%) of BC and 9 out of 25 (36%) of BBD (P = 0.02)
had signs of thyroid autoimmunity consistent with the hypoechogenic pattern of thyroid gland associated or not
with TAb; 2 out of 36 (5.55%) of BC and 1 out of 25 (4%) of BBD patients had autoimmune hypothyroidism and no
hypothyroidism was found in controls.
CONCLUSIONS: The results of this study confirm the strong relation between thyroid autoimmunity and BC. This
finding is independent of stressful events represented by surgery or anaesthetic procedures. The present data
call attention to the usefulness of screening for autoimmune thyroid disorders in patients with nodular breast
disease selected for surgery.
Association between breast cancer and autoimmune thyroid disorders: no increase of lymphocytic infiltrates in
breast malignant tissues.
Fierabracci P, Pinchera A, Campani D, Pollina LE, Giustarini E, Giani C.
J Endocrinol Invest. 2006 Mar;29(3):248-51.
[abstract only]
An association between thyroid autoimmunity and breast cancer (BC) has been consistently reported, but the
cause of this association is still unknown. The role of lymphocytic infiltration (LI) in breast tumorigenesis is
controversial and several data suggest that in BC an increase of lymphoid cell infiltrates or a dysfunctional local
immune response may be detected very early during tumor development. Chronic autoimmune thyroiditis is
characterized by different degrees of LI in thyroid gland and BC cells share some antigenic properties similar to
those detected in thyroid tissue, such as sodium iodide symporter (NIS) and peroxidase activity.
The aim of this study was to evaluate the frequency and amount of LI in malignant and in normal peritumoral
breast tissues, as expression of autoimmune morphological changes, in a group of BC patients with thyroid
autoimmunity. We suppose that an increased LI in breast tissues of this group of patients may help explain the
association between BC and thyroid autoimmunity.
The study group included 26 BC patients with thyroperoxidase antibodies positivity (TPOAb+), 14 of them (53.8%)
with Hashimoto's thyroiditis (HT), and 30 BC patients with no evidence of thyroid autoimmune disorders.
Malignant and surrounding normal breast tissues were assessed for LI. The amount of LI was scored as very
scanty or scanty (LI S) and moderate or marked (LI M), independently by two expert pathologists.
LI S was detected in 19/26 (73.1%) BC tissues from patients with TPOAb positivity and LI M in 7 (26.9%). All BC
patients with HT had LI S. LI S was detected in 25/30 (83%) and LI M in 5/30 (17%) of BC tissue from patients with
no thyroid autoimmunity. The difference in the amount of LI of BC tissues in patient with or without autoimmune
thyroid disorders was not significant. The LI was generally absent or very scanty in remote breast tissue in all
cases.
In conclusion, in breast malignancies the presence of humoral and/or clinical evidence of thyroid autoimmunity is
not associated to autoimmune morphological changes of cancer and peritumoral normal tissue. The LI does not
seem to have any role in tumorigenesis in patients with BC and thyroid autoimmunity.
Absence of interference of serum IgGs from patients with breast cancer and thyroid autoimmunity on the
function of human iodide symporter gene stably transfected in CHO cells.
Fierabracci P, Pinchera A, Tonacchera M, Agretti P, De Marco G, Albertini S, Conforti G, Seregni E, Agresti R,
Grasso L, Giani C.
J Endocrinol Invest. 2004 Oct;27(9):862-5.
[abstract only]
The cause of the association between breast cancer (BC) and thyroid autoimmunity is still unknown. Na+/I-
symporter (NIS) is highly expressed in BC cells, and previous studies demonstrated that iodine content in BC is
lower than in remote normal breast tissue, suggesting a disorder of iodide uptake in BC.
In this study, we evaluated the presence of putative serum autoantibodies able to block the function of NIS in BC
patients with thyroid autoimmunity. IgGs were obtained from: a) 11 patients with BC and high antithyroglobulin
(TgAb) and antithyroperoxidase (TPOAb) autoantibodies serum concentration; b) 34 patients with Hashimoto's
thyroiditis (HT) (1 was euthyroid, 4 had subclinical hypothyroidism and 29 were overtly hypothyroid); c) 15 control
subjects. The biological activity of NIS was studied using a chinese hamster ovary (CHO) cell line stably
expressing NIS (NIS-CHO). The course of iodide accumulation in NIS-CHO was studied after addition of Na125 I in
culture medium.
The accumulation of iodide linearly increased between 2 and 10 min, reaching a plateau at 45 min. The
preincubation of NIS-CHO with IgGs purified from sera of BC with the highest levels of TPOAb and TgAb caused
an inhibition of iodine uptake of no more than 5%. Similar results were obtained using IgGs purified from patients
with HT and control subjects.
Our data showed no interference of autoantibodies on iodine uptake in patients with BC and thyroid autoimmunity
and the very low percentage of inhibition of iodine uptake cannot explain the lower content of iodine in BC tissue.
Relationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast
malignancy.
Giani C, Fierabracci P, Bonacci R, Gigliotti A, Campani D, De Negri F, Cecchetti D, Martino E, Pinchera A.
J Clin Endocrinol Metab. 1996 Mar;81(3):990-4.
The relationship between thyroid dysfunction and breast cancer (BC) is debated. To clarify this controversial
issue, a prospective study on thyroid function in BC was performed.
The prevalence of thyroid disease was examined in 102 consecutive BC patients with ductal infiltrating
carcinoma after surgery and before starting any chemohormonal or x-ray therapy and in 100 age-matched
control healthy women living in the same borderline iodine-sufficient geographic area. All subjects were
submitted to clinical ultrasound thyroid evaluation and serum free T4, free T3, TSH, thyroperoxidase antibody,
and thyroglobulin antibody determination. Fine needle aspiration was performed in all thyroid nodules. Estrogen
and progesterone receptors (ER and PR, respectively) were assayed in 92 and 55 BC specimens, respectively.
The overall prevalence of thyroid disease was 47 in 102 (46%) in BC patients and 14 in 100 (14%) in controls (P <
0.0001). The prevalence of nontoxic goiter was 27.4% in BC patients and 11% in controls (P = 0.003). Hashimoto's
thyroiditis was found in 13.7% of BC patients and in only 2% of the controls (P < 0.005). Other thyroid disorders
found in the BC group included 2 cases of Graves' disease, 2 of thyroid carcinoma, and 1 of subacute thyroiditis,
whereas in the control group only 1 case of Graves' disease and none of the other disorders were found. Mean
free T3, free T4, and TSH concentrations showed no difference between BC patients and controls. The
prevalence of thyroperoxidase antibody was higher in BC patients than in controls (23.5% vs. 8%; P < 0.005),
whereas the prevalence of thyroglobulin antibody was not different. In BC patients the presence of thyroid
antibodies was more frequently associated with clinically detectable autoimmune thyroiditis (14 of 26, 51.8%; P =
0.03) and was more common in the younger group. The positivity of ER was found in 51 of 92 (55.43%) and that of
PR was found in 26 of 55 (47.27%) BC specimens. No relationship was found among ER, PR status, and the
presence of serum thyroid antibodies.
In conclusion, 1) the present study provides evidence that the overall prevalence of thyroid disorders is
increased in patients with breast cancer, and 2) thyroid autoimmune disorders, especially Hashimoto's
thyroiditis, account to a large extent for the increased prevalence of thyroid disease in patients with breast
cancer. This feature is independent from the ER and PR status of the primary tumor. The present findings call
attention to the usefulness of screening for thyroid disease in any patient with breast cancer.
HARTMANN
Benign breast disease and the risk of breast cancer.
Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS,
Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJ 3rd, Visscher DW.
N Engl J Med. 2005 Jul 21;353(3):229-37.
BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We studied a large group of
women with benign breast disease to obtain reliable estimates of this risk.
METHODS: We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic
between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To
estimate relative risks, we compared the number of observed breast cancers with the number expected on the
basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry.
RESULTS: We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative
lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4
percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56
(95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy.
The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with
a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of
1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history
of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No
increased risk was found among women with no family history and nonproliferative findings. In the first 10 years
after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia.
CONCLUSIONS: Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic
classification of a benign breast lesion and a family history of breast cancer.
HOWENSTINE
Thyroid Hormone Therapy Appears to Cause Breast Cancer
Dr. James Howenstine, MD.
NewsWithViews.com July 27, 2006
When humans lack iodine the thyroid gland enlarges (goiter), nodules appear in the thyroid gland and over a
period of time cancer may appear in a thyroid nodule. Conventional medicine treats thyroid gland enlargement
with thyroid hormone without considering the possibility that the hypothyroidism and goiter may be due to lack of
iodine. This failure to diagnose and treat iodine deficiency can lead to an increased risk of breast cancer and the
longer the diagnosis is missed the greater the chance that breast cancer will occur. Women taking thyroid
hormone appear to be twice (12.1%) as likely to develop breast cancer as women not using thyroid hormone (6..
2%). Women who had taken thyroid hormone for 15 years had a 19.5% incidence of breast cancer whereas
women who have only taken thyroid hormone for 5 years had only a 10% incidence of breast cancer.
IWAMOTO
The Mechanistic Role of Iodine in Breast Carcinogenesis
Iwamoto KS
US Army Medical Research and Materiel Command, October 2005.
There is both considerable interest and ignorance in the possible role of iodine in the etiology and prognosis of
breast cancer. This project is the first step in elucidating a mechanistic role for iodine in breast carcinogenesis.
The data that we have been able to generate to date suggest that our hypothesis is correct; namely, using
transgenic human breast cancer cells (MCF7) overexpressing the sodium/iodide symporter (NIS) and/or
lactoperoxidase (LPO), we have shown that NIS facilitates death or survival pathways following irradiation, a
known human breast carcinogen, depending on the presence or absence of iodine, respectively, and that this
switching can be modulated by the cell's ability to organify and stabilize the iodine via LPO. Further, we have
shown that expression of both NIS and LPO will radiosensitize the MCF7 cells while NIS alone will make them
radioresistant and more aggressive. These data agree with observations made by others demonstrating that
iodine deficiency is correlated with increased breast cancer incidence, and that a large percentage of human
breast cancers overexpress NIS. Additionally, the fact that NIS and LPO are most active in the mammary glands
during late pregnancy and lactation may explain the well established observation that early and frequent parity
and long lactation history reduce the risk for breast cancer development. We are confident that the data from the
experiments currently in progress should help to strengthen our already existing results. Clarification of these
issues should foster future studies not only in breast cancer diagnosis and therapy but also in prevention
through conscious changes in diet and environment.
KAPDI
Breast cancer. Relationship to thyroid supplements for hypothyroidism.
Kapdi CC, Wolfe JN.
JAMA. 1976 Sep 6;236(10):1124-7.
This study was undertaken to determine the relationship between thyroid supplements and breast cancer. The
incidence of breast cancer among the patients who received thyroid supplements was 12.13%, while in the
control group it was 6.2%. The incidence rate of breast cancer was 10%, 9.42%, and 19.48% among patients who
received thyroid supplements for one to five, 5 to 15, and for more than 15 years, respectively. The incidence of
breast cancer among nulliparous women who received thyroid supplements was 33%, while in the nulliparous
women without thyroid supplements the incidence was only 9.25%. Even in a specific age group, the incidence
rate of breast cancer was higher among patients receiving thyroid supplements, when compared to the control
patients in the same age group.
KESSLER
Aqueous Iodine Equilibria in Mammalian Iodination Reactions
Kessler J, Hooge D
Thyroid, Jan 2007, Vol. 17, No. 1 : 19 -24
Regulatory activity has been demonstrated in two classes of iodinated organic species: thyroid hormones (T3
and T4) and iodinated lipids (ILs), e.g. 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid. The formation of iodinated
biomolecules requires iodide oxidation. In mammals iodide oxidation is one of several peroxidase-mediated
reactions that serve to reduce hydrogen peroxide. I2 is one of several reaction products formed by mammalian
peroxidases during iodide oxidation. I2 forms HOI in an aqueous environment which also has the capacity to
iodinate organic species. This manuscript examines the potential relationship between the two classes of
known mammalian iodinating species. A model describing iodination pathways for organic species in mammals
is advanced. The model predicts the formation of ILs under normal dietary intake of iodine. The model was
challenged by characterizing the lipids of hogs maintained on a diet containing normal levels of iodine. Iodinated
lipids were found to be present in the fatty acids extracted from the thyroid of these hogs.
The Effect of Supraphysiologic Levels of Iodine on Patients with Cyclic Mastalgia
Kessler JH.
Breast J. 2004 Jul-Aug;10(4):328-36.
A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted with 111 otherwise
healthy euthyroid women with a history of breast pain.... A statistically significant improvement (p < 0.01)
associated with dose was observed in the Lewin overall pain scale for all treated groups compared to placebo.
Reductions in all three physician assessments were observed in patients after 5 months of therapy in the 3.0
mg/day (7/28; 25%) and 6.0 mg/day (15/27; 18.5%) treatment groups, but not the 1.5 mg/day or placebo group.
Patients recorded statistically significant decreases in pain by month 3 in the 3.0 and 6.0 mg/day treatment
groups, but not the 1.5 mg/day or placebo group; more than 50% of the 6.0 mg/day treatment group recorded a
clinically significant reduction in overall pain. All doses were associated with an acceptable safety profile. No
dose-related increase in any adverse event was observed.
IoGen - Breast Pain Clinical Research Trial
Symbollon is enrolling patients in a national multi-center, placebo-controlled, double-blinded, randomized Phase
III clinical trial for the treatment of moderate or severe breast pain associated with fibrocystic breast disease.
The trial drug, IoGen, may help relieve breast pain. The study has been registered with FDA under the Protocol
Registration System at ClinicalTrials.gov.
Symbollon provides update on IoGen Phase III Pain Study
Symbollon
August 9, 2006
It anticipates closing the enrollment of its IoGen™ Phase III pivotal pain study by yearend. The ongoing IoGen
study has over 25 active sites across the United States. Symbollon is planning to conduct a comprehensive
advertising campaign during the remainder of 2006 to assist these sites in recruiting subjects for the study by
yearend.
Research calls for use of molecular iodine to treat breast cancer
Symbollon
October 31, 2006
Symbollon Pharmaceuticals, Inc. (OTCBB: SYMBA) today provided a review of recent independent scientific
publications focused on the possible use of molecular iodine, the active agent in Symbollon’s drug, IoGen™, to
treat breast cancer. The results of such research identify molecular iodine as a possible treatment for breast
cancer. This research recommends the initiation of human clinical trials testing molecular iodine as an adjuvant
therapy for breast cancer.
Iodine's Mechanism of Action (link to paper is no longer available on the internet)
Kessler J
The relationship between iodine intake, thyroid hormones and breast cancer has engaged the interest of
clinicians for well over 50 years. Within the past thirty years diverse experimental observations examining (1) the
autoregulatory mechanism in the thyroid, (2) the dynamic control of pituitary derived prolactin in patients with
fibrocystic breast disease and (2) aqueous iodine chemistry, have provided a mechanistic basis that for the
variety of epidemiological, non-clinical and clinical observations related to iodine intake and mammary tissue.
The thyroid needs a mechanism to protect itself from chronic exposure to high levels of iodine. Observations
from a variety of different laboratories indicate that the enzyme peroxidase catalyzes the formation of iodinated
polyunsaturated fatty acids, such as arachidonic acid and docosahexaenoic acids, instead of tyrosine at
elevated concentrations of iodide. Several of the iodinated lipids formed by peroxidase have been shown to
exhibit a broad antiproliferative effect. Iodolactones have been shown to inhibit the production of inositol
phosphates induced by epidermal growth factor (EGF); the hydrogen peroxide production by NADPH oxidases;
and adenylyl cyclase. Several leading researchers in this field believe that the antiproliferative activity of
iodolactones and iodoaldehyes mediate thyroid autoregulation. These iodolipids should be able to be formed in
other tissues of the body.
The formation of these iodinated lipids is reasonable based upon the enzymology of peroxidase and aqueous
iodine chemistry. The mechanism of the enzyme peroxidase has been studied for close to 100 years. Between
1940 and 1990 many teams of expert enzymologists around the world attempted to identify how peroxidase
catalyzes the formation of thyroid hormones. Despite thousands of published studies we cannot identify a
discrete set of experiments that unequivocally identify the mechanistic pathway for thyroid hormone synthesis.
An overlooked factor that probably contributes to this difficulty is the characteristics of the oxidized iodide. Hatch
developed the first complete set of equations that describe the behavior of the I2 species in an aqueous
environment. In the 1980s Gottardi developed a computer program that solves the nonlinear equations
describing this equilibrium. It is clear from Gottardi's studies that oxidized iodide species do not behave in a
linear manner. That is, the reaction product(s) from the oxidation of iodide by peroxidase can vary depending
upon the concentration of the reactants. It is not, therefore, unreasonable that at physiologic levels of iodide
tyrosine is iodinated while at elevated levels other iodine species, like I2, are formed. Peroxidase mediated
formation of iodinated lipids at elevated iodide concentrations is reasonable from the perspective of iodine
chemist since molecular iodine (I2) formation could be expected under these conditions. In fact, Symbollon has
used this reaction as the basis of the first product developed by the company
The requirements for the formation of iodinated lipids are (1) a peroxidase, (2) an elevated concentration of
iodide and (3) hydrogen peroxide. These conditions can be met in the mammary gland, oviduct and uterus.
Symbollon Patents for Breast Iodine
6248335 Stabilized oral pharmaceutical composition containing iodide and iodate and...
KOGAI
Enhancement of sodium/iodide symporter expression in thyroid and breast cancer.
Kogai T, Taki K, Brent GA.
Endocr Relat Cancer. 2006 Sep;13(3):797-826.
The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA
and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is
usually reduced resulting in the characteristic finding of a 'cold' or non-functioning lesion on a radioiodine image.
Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated
thyroid cancer to utilize beta-emitting radioactive iodide for the treatment of residual and metastatic disease.
Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human
thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma
membrane, increasing radioiodide uptake. Approximately 10-20% differentiated thyroid cancers, however, do not
express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis.
Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal
promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer
specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various
nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A
wide range of 'differentiation' agents have been utilized to stimulate NIS expression in thyroid and breast cancer
using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to
stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene
regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in
thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor
differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in 'scan-negative'
thyroid cancer and some breast cancer.
Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse
breast cancer models.
Kogai T, Kanamoto Y, Che LH, Taki K, Moatamed F, Schultz JJ, Brent GA.
Cancer Res. 2004 Jan 1;64(1):415-22.
Lactating breast tissue and some breast cancers express the sodium/iodide symporter (NIS) and concentrate
iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and iodide
accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we
investigated the in vivo efficacy and specificity of tRA-stimulated iodide accumulation in mouse breast cancer
models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide
accumulation in the xenograft tumors was markedly increased, approximately 15-fold greater than levels
without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not
significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors
was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced
in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These
data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term
systemic retinoic acid, followed by radioiodide administration, is a potential tool in the diagnosis and treatment of
some differentiated breast cancer.
Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast
cancer cell line.
Kogai T, Schultz JJ, Johnson LS, Huang M, Brent GA.,
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8519-24.
The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be
active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells,
an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment
stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold above baseline.
Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by
retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein (
approximately 68 kDa). tRA stimulated NIS gene transcription approximately 4-fold, as shown by nuclear run-on
assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer
cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7
cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide
retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with (131)I after tRA
stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast
cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis
and treatment of some differentiated breast cancers.
LIM, MOON
Enhanced Expression of Adenovirus-Mediated Sodium Iodide Symporter Gene in MCF-7 Breast Cancer Cells with
Retinoic Acid Treatment.
Lim SJ, Paeng JC, Kim SJ, Kim SY, Lee H, Moon DH.
J Nucl Med. 2007 Mar;48(3):398-404.
[abstract only]
Increased expression of the sodium iodide symporter (NIS) is required for effective radioiodine treatment and
reporter gene imaging of breast cancer. We investigated the effect of retinoic acid on adenovirus-mediated
expression of the human NIS gene in the MCF-7 breast cancer cell line.
METHODS: The MCF-7 cell line was infected with recombinant adenovirus carrying the human NIS gene (Rad-NIS).
Levels of NIS messenger RNA (mRNA) and protein expression and radioiodine ((125)I) uptake were measured to
evaluate adenovirus-mediated NIS gene expression in wild-type and Rad-NIS-infected MCF-7 cells after treatment
with all-trans-retinoic acid (ATRA; 10(-8)-10(-6) mol/L).
RESULTS: The transduction efficiency of adenovirus in MCF-7 cells at a multiplicity of infection (MOI) of 50 was
>60%. After incubation with 10(-6) mol/L ATRA, the mRNA level in Rad-NIS-infected MCF-7 cells increased to 118.5
times that of wild-type MCF-7 cells, whereas the mRNA level in wild-type MCF-7 cells showed only a 2.1-fold
increase. Western blot, immunocytochemical staining, and flow cytometry analyses showed that NIS protein
expression in MCF-7 cells infected with Rad-NIS increased after ATRA treatment. With ATRA treatment, the
amount of (125)I uptake increased in a dose-dependent manner (P < 0.001). The (125)I uptake in wild-type MCF-7
cells increased 3.1-, 5.5-, and 7.6-fold with treatment with 10(-8), 10(-7), and 10(-6) mol/L ATRA, respectively. Rad-
NIS-infected cells showed a 4.0-fold increase in (125)I uptake. Treatment of Rad-NIS-infected cells with 10(-8), 10
(-7), and 10(-6) mol/L ATRA increased (125)I uptake by 4.9-, 8.2-, and 27.6-fold, respectively, compared with wild-
type MCF-7 cells. The level of NIS expression in Rad-NIS-infected MCF-7 cells treated with 10(-6) mol/L ATRA
(245.0 +/- 13.7 pmol/10(6) cells) was much greater than the sum of the expression levels seen in ATRA-treated
wild-type cells and Rad-NIS-infected wild-type cells.
CONCLUSION: Retinoic acid increases adenovirus-mediated NIS expression in MCF-7 cells. Our results indicate
that improved efficiency of NIS gene therapy or reporter imaging in breast cancer may be possible with retinoic
acid treatment.
NATARAJAN
Role of lipoxygenases in breast cancer.
Natarajan R, Nadler J.
Front Biosci. 1998 Jun 8;3:E81-8. Review.
[abstract only]
The interaction of growth factors such as epidermal growth factor (EGF) with their receptors on breast cancer
cells can lead to the hydrolysis of phospholipids and release of fatty acids such as arachidonic acid which can
be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate
oncogenes and have mitogenic and chemotactic effects. The 12-LO product, 12-hydroxyeicosatetraenoic acid (12
(S)HETE), has been shown to play a key role in mediating several steps of the process of hematogenous
metastasis and tumor cell adhesion. 12-LO can also be activated by several growth factors and inflammatory
cytokines. A growing body of evidence suggests that specific metabolites of arachidonic and/or linoleic acid
serve as central elements in signal pathways necessary for cell mitogenesis as induced by growth factors or
oncogenic transformation. This review examines the role of LOs in breast cancer. The growth of breast cancer
cells has been shown to increased by certain LO products and, LO pathway inhibitors could block the growth of
some breast cancer cells. 12-LO activity and expression was increased in breast cancer tissues relative to the
uninvolved normal tissue, and also in cultured breast cancer cells relative to normal breast cells. Treatment of
the breast cancer cell line, MCF-7 cells, with epidermal growth factor (EGF), led to significant increases in 12-LO
activity and expression. Thus, activation of the 12-LO pathway may play a key role in basal and EGF-induced
breast cancer cell growth.
Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor.
Natarajan R, Esworthy R, Bai W, Gu JL, Wilczynski S, Nadler J.
J Clin Endocrinol Metab. 1997 Jun;82(6):1790-8.
The interaction of growth factors, such as epidermal growth factor (EGF) with their receptors, on breast cancer
cells can lead to the hydrolysis of phospholipids and release of fatty acids, such as arachidonic acid, which can
be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate
oncogenes and have mitogenic and chemotactic effects. In this study, we have evaluated the regulation of 12-LO
activity and expression in breast cancer cells and tissues. Leukocyte-type 12-LO messenger RNA (mRNA)
expression was studied by a specific RT-PCR method in matched, normal, uninvolved and cancer-involved breast
tissue RNA samples from six patients. In each of these six patients, the cancer-involved section showed a much
higher level of 12-LO mRNA than the corresponding normal section. 12-LO mRNA levels also were greater in two
breast cancer cell lines, MCF-7 and COH-BR1, compared with the nontumorigenic breast epithelial cell line, MCF-
10F. The growth of the MCF-7 cells was significantly inhibited by two specific LO blockers but not by a
cyclooxygenase blocker. Treatment of serum-starved MCF-7 cells with EGF for 4 h led to a dose-dependent
increase in the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid. EGF treatment also increased
the levels of the leukocyte-type 12-LO protein expression at 24 h. These results suggest that activation of the 12-
LO pathway may play a key role in basal and EGF-induced breast cancer cell growth.
PARK
Sonographic detection of thyroid cancer in breast cancer patients.
Park JS, Oh KK, Kim EK, Son EJ, Chang HS, Hong SW, Moon HJ, Kwack KS.
Yonsei Med J. 2007 Feb 28;48(1):63-8.
[abstract only]
The purpose of our study was to analyze the incidence of incidental thyroid cancers which were detected by
simultaneous sonographic examination of breast and thyroid glands. Between January 2001 and March 2004,
518 patients were diagnosed with breast cancer after modified radical mastectomy (n=369) or breast
conserving surgery (n=149). We screened thyroid glands when we examined breast for diagnosis and follow-up
after surgery. If we found the sonographic finding of suspicious for malignancy in thyroid, we immediately
performed ultrasound-guided fine needle aspiration biopsy (FNAB). Forty-two cases showed suspicious
sonographic findings and of those, 18 cases (42.9%) were determined to have suspicious malignant cytology by
ultrasound guided FNAB. Among 518 breast cancers, total 13 cases (2.5%) were diagnosed with papillary
carcinoma after thyroidectomy. The mean longest diameter of the thyroid masses was 9.9mm (range 1-30mm).
Six cases (6/13, 46.2%) were diagnosed as simultaneous breast and thyroid cancers, and the rest of the thyroid
cancers were detected after 6 to 33 months (mean 16.5 months) after surgery. In conclusion, the patients with
breast cancer had a high incidence (2.5%) of thyroid cancer. Sonographic screening is useful for the early
detection of thyroid cancer.
PERRON
Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues.
Perron B, Rodriguez AM, Leblanc G, Pourcher T.
J Endocrinol. 2001 Jul;170(1):185-96.
Iodide concentration in milk by mammals is a necessary step for thyroid hormone synthesis by the newborn.
With the purpose of using the mouse as an animal model to analyse the role of the sodium iodide symporter (NIS)
in iodide transport and its regulation in the mammary gland, mouse NIS (mNIS) cDNA was isolated from lactating
mice. The cloned sequence shows an open reading frame of 1854 nucleotides encoding a protein of 618 amino
acids highly homologous to the rat and human NIS (95% and 81% identity respectively). Expression of mNIS in
cultured mammalian cells induced cellular iodide accumulation. This iodide uptake process is sodium dependent
and inhibited by thiocyanate and perchlorate. Tissue distribution analysis revealed that mNIS mRNAs are
predominantly expressed in thyroid, stomach and in the lactating mammary gland and are present to a lower
extent in several other tissues. Our data show for the first time that the level of mNIS mRNA is upregulated in the
mammary gland during lactation.
RILLEMA
Pendrin transporter carries out iodide uptake into MCF-7 human mammary cancer cells.
Rillema JA, Hill MA.
Exp Biol Med (Maywood). 2003 Oct;228(9):1078-82.
Previous studies have shown that iodide is actively taken up into mammary alveolar epithelial cells and secreted into
milk. In the present studies we demonstrate that 125I also accumulates in MCF-7 cells against a concentration
gradient; distribution ratios of greater than 30 were achieved. Iodide uptake into MCF-7 cells is transient, with peak
accumulations occurring in about 5 min. The iodide is rapidly metabolized, probably to iodine, and it then exits the
cells. The iodide transporter identified in MCF-7 cells is pendrin. DIDS, a nonspecific inhibitor of anion exchange,
inhibits iodide uptake. Iodide uptake is impaired at reduced temperature, but is not dependent on sodium. Inhibitors
of the sodium-iodide symporter (NIS) as well as ouabain did not affect the extent of iodide uptake. The pendrin
transporter but not NIS was identified via western blotting techniques. Pendrin appears to be the primary iodide
transporter in the MCF-7 cell line stocks that were employed for these studies.
Prolactin regulation of the pendrin-iodide transporter in the mammary gland.
Rillema JA, Hill MA.
Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E25-8. Epub 2002 Sep 11.
Iodide is an essential constituent of milk that is present in concentrations more than an order of magnitude higher
than in the maternal plasma. Earlier, a sodium-iodide symporter was identified in the mammary gland; this
transporter is presumed to take iodide from the maternal plasma into the alveolar epithelial cells of the mammary
gland. We now report the existence of a second iodide transporter, pendrin, which is also essential for iodide
accumulation in milk. Via Western blotting methods, high levels of the transporter were detected in lactating tissues;
lesser amounts were found in tissues from midpregnant and virgin mice. Prolactin, at physiological concentrations,
stimulated the expression of the pendrin transporter in cultured mammary tissues taken from 12- to 14-day-pregnant
mice. The prolactin effect on iodide uptake into cultured mammary tissues was abolished by pendrin transport
inhibitors, including DIDS, furosemide, and probenecid. These studies suggest that the prolactin stimulation of
pendrin activity is an essential element in the prolactin stimulation of iodide uptake into milk.
Breast pg 4 (cont)
FLECHAS
Breast Health: Iodine and Other Nutrients Play a Crucial Role
Flechas JD
Back in the early 1990s it was noted that patients who had iodine deficiency had associated benign breast changes.
By giving these patient’s iodine the breast changes that were present would regress. It had been noticed a few years
earlier that in animal studies, where the animal had been denied access to iodine, the animals developed benign
breast changes like humans.In animal studies, researchers have been able to produce breast cancer in animals by
depriving them of iodine.
"In my own personal medical practice I have literally seen the regression of cysts, nodules, scar tissue, and painful
breast with the use of 50 mg of Iodoral® per day for 2-3 years. The breast pain goes away in just a few weeks, but the
cyst/cysts, scar tissue and breast nodules take up to 2 to 3 years to resolve. On mammograms I have seen a 50 to 80
percent reduction in the scar tissue present in the breast. Studies are needed to show via biopsy that the many
different types of FBD will regress with iodine supplementation.
"Before starting on iodine therapy, a patient should have their thyroid hormone values investigated. A doctor should
check the size of the thyroid for enlargement and or nodules. An iodine-loading test should also be done prior to
starting iodine therapy to establish the need for iodine therapy. In this test the patient is given 50 mg of iodine and a
24-hour urine test is then collected. The iodine level in the urine is measured. The more saturated the body is with
iodine the higher the level of iodine excreted. The more saturated the body is, the less breast abnormalities have
been seen. The test is repeated at 3 months to document increasing saturation. If saturation is not occurring then
further investigation is called for to find out why saturation isn’t happening.
FUNAHASHI
Seaweed prevents breast cancer?
Funahashi H, Imai T, Mase T, Sekiya M, Yokoi K, Hayashi H, Shibata A, Hayashi T, Nishikawa M, Suda N, Hibi Y,
Mizuno Y, Tsukamura K, Hayakawa A, Tanuma S.,
Jpn J Cancer Res. 2001 May;92(5):483-7.
To investigate the chemopreventive effects of seaweed on breast cancer, we have been studying the relationship
between iodine and breast cancer. We found earlier that the seaweed, wakame, showed a suppressive effect on the
proliferation of DMBA (dimethylbenz(a)anthracene)-induced rat mammary tumors, possibly via apoptosis induction. In
the present study, powdered mekabu was placed in distilled water, and left to stand for 24 h at 4 degrees C. The
filtered supernatant was used as mekabu solution. It showed an extremely strong suppressive effect on rat
mammary carcinogenesis when used in daily drinking water, without toxicity. In vitro, mekabu solution strongly
induced apoptosis in 3 kinds of human breast cancer cells. These effects were stronger than those of a
chemotherapeutic agent widely used to treat human breast cancer. Furthermore, no apoptosis induction was
observed in normal human mammary cells. In Japan, mekabu is widely consumed as a safe, inexpensive food. Our
results suggest that mekabu has potential for chemoprevention of human breast cancer.
Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in
rats
Funahashi H, Imai T, Tanaka Y, Tsukamura K, Hayakawa Y, Kikumori T, Mase T, Itoh T, Nishikawa M, Hayashi H,
Shibata A, Hibi Y, Takahashi M, Narita T.
Jpn J Cancer Res. 1999 Sep;90(9):922-7.
We examined the anti-tumor proliferation effects of wakame seaweed on 7,12-dimethylbenz(a)-anthracene (DMBA)-
induced rat mammary tumor….Significant suppression of tumor growth was observed in groups I-B and I-C
compared with I-A. In groups I-B and I-C, the weights of resected mammary tumors were significantly lower and
serum total iodine concentration was significantly higher than in I-A. BrdU indices were significantly lower in groups I-
B and I-C, compared with I-A. TGF-beta and apoptotic index were inversely related to BrdU. These results suggest
that iodine is transported from the serum into mammary tissues and induces apoptosis through the expression of
TGF-beta. In conclusion, wakame suppressed the proliferation of DMBA-induced mammary tumors.
Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat.
Funahashi H, Imai T, Tanaka Y, Tobinaga J, Wada M, Morita T, Yamada F, Tsukamura K, Oiwa M, Kikumori T, Narita
T, Takagi H.,
J Surg Oncol. 1996 Mar;61(3):209-13.
Concerning the suppressive effect of inorganic iodine on the growth of 7,12-dimethyl-benz(a)anthracene (DMBA)-
induced breast tumor in female Sprague-Dawley (SD) rats, we previously reported that although iodine itself had a
suppressive effect on the tumor growth, its effect was not as strong as that of MPA (medroxy-progesterone acetate).
However, the combined medication of iodine at a low concentration + MPA showed a stronger effect than MPA alone.
The purpose of the present study is to elucidate this mechanism of action by determining the uptake of the
administered iodine into breast tumor tissue. Breast tumors were induced with DMBA in female SD rats, and these
animals were treated with MPA + inorganic iodine at various concentrations for 4 weeks to determine tumor growth
and tumor iodine content. In the comparison of tissue iodine content in growth-suppressive tumors with that in
nonsuppressive tumors, the former showed a much higher iodine content. This suggests that direct uptake of
inorganic iodine by breast tumors led to the suppression of tumor growth.
GARCIA-SOLIS
Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by molecular iodine (I2) but not by iodide (I-)
treatment Evidence that I2 prevents cancer promotion.
Garcia-Solis P, Alfaro Y, Anguiano B, Delgado G, Guzman RC, Nandi S, Diaz-Munoz M, Vazquez-Martinez O, Aceves C.
Mol Cell Endocrinol. 2005 May 31;236(1-2):49-57. Epub 2005 Apr 13.
We analyzed the effect of molecular iodine (I2), potassium iodide (KI) and a subclinical concentration of thyroxine (T4)
on the induction and promotion of mammary cancer induced by N-methyl-N-nitrosourea. Virgin Sprague-Dawley rats
received short or continuous treatment. Continuous I2 treated rats exhibited a strong and persistent reduction in
mammary cancer incidence (30%) compared to controls (72.7%). Interruption of short or long term treatments
resulted in a higher incidence in mammary cancer compared to the control groups. The protective effect of I2 was
correlated with the highest expression of the I-/Cl- transporter pendrin and with the lowest levels of lipoperoxidation
expression in mammary glands. Triiodothyronine serum levels and Na+/I- symporter, lactoperoxidase, or p53
expression did not show any changes. In conclusion continuous I2 treatment has a potent antineoplastic effect on the
progression of mammary cancer and its effect may be related to a decrease in the oxidative cell environment.
Differential uptake and signaling or molecular iodine (I2) in lactating, virgin, or neoplastic mammary glands
Garcia-Solis P, Delgado G, Anguiano B, Aceves C
13th International Thyroid Meeting, Buenos Aires, Arg. (Abstract) Thyroid 15 (Suppl 1) S-128.
[abstract only]
Conclusion: 1) I2 is differentially taken up by lactating, virgin and neoplastic MG [mammary gland], suggesting the
existence of mammary iodine uptake pathways in addition to NIS and PEN. 2) Gene expression of thyroid and MG is
differentially regulated by I2.
5'Deiodinase in two breast cancer cell lines: effect of triiodothyronine, isoproterenol and retinoids.
Garcia-Solis P, Aceves C.
Mol Cell Endocrinol. 2003 Mar 28;201(1-2):25-31.
Abstract only
Thyroid hormones participate in the regulation of growth, development and energy expenditure of vertebrates. Type I
(D1) and type II 5'deiodinases catalyze the peripheral conversion of the thyroid prohormone thyroxine to the active
form triiodothyronine (T3). D1 is expressed in organs like liver, thyroid, and lactating mammary gland. This enzyme is
regulated in an organ-specific manner by a wide number of factors like carbohydrates, T3, thyrotropin, and
catecholamines. However, it has been shown that in several types of cancer the expression of D1 is reduced, lost, or
regulated by different components. In the present work we describe the expression and regulation of 5'deiodinases
in two breast cancer cell lines: MCF-7 (ovarian hormone-dependent) and MDA-MB-231 (ovarian hormone-
independent). Our results showed that MCF-7 cells expressed D1 activity ( approximately 10 pmol I(-)/mg protein per
h), which was stimulated only by retinoic acid treatments, but not by T3 or the beta-adrenergic agonist isoproterenol.
In MDA-MB-231 cells, deiodinase activity was not detected in control conditions nor under any of these treatments.
These results support the notion that D1 expression could represent a sensitive differentiation marker.
GIANI
Thyroid autoimmunity in patients with malignant and benign breast diseases before surgery.
Giustarini E, Pinchera A, Fierabracci P, Roncella M, Fustaino L, Mammoli C, Giani C.
Eur J Endocrinol. 2006 May;154(5):645-9.
[abstract only]
BACKGROUND: Previous studies have demonstrated a high prevalence of thyroperoxidase antibodies (TPOAb)
and autoimmune hypothyroidism in breast cancer (BC). These studies have been performed in BC patients
generally 20-30 days after mastectomy. It is known that stress may have an influence on the immune system and
a relation between stressful events and the onset or worsening of autoimmune thyroid disorders has been
reported by several authors. The aim of the study was to evaluate the prevalence of autoimmune thyroid disease
in patients with nodular breast disease selected for surgery before any treatment. Our hypothesis was that the
high prevalence of thyroid autoimmune disorders in BC is independent of stressful events represented by
surgery and/or anaesthetic procedures.
METHODS: Our series included 61 consecutive women aged 52.8 +/- 10.2 yrs (mean age +/- s.d.) with nodular
breast disease selected for breast surgery: 36 out of 61 of them (59%) had BC and 25 out of 61 had benign breast
disease (BBD). Controls included 100 healthy age-matched women. All patients and control subjects were
submitted to clinical, ultrasound thyroid evaluation and serum-free thyroxine (FT4), serum-free tri-iodothyronine
(FT3), TSH, TPOAb and thyroglobulin antibodies (TgAb) determination.
RESULTS: Mean FT3, FT4 and TSH concentration showed no differences between BC patients, BBD patients and
controls. The prevalence of TPOAb in BC patients (12/36: 33.33%) was significantly higher than in BBD patients
(5/25: 20%) (P < 0.01) and in controls (8/100: 8%) (P < 0.01). Similarly, the prevalence of TgAb in BC patients was
12 out of 36 (33.33%) significantly higher than that detected in BBD patients (4/25: 16%) (P < 0.01) and in controls
(12/100: 12%) (P < 0.01). Of the 36 BC patients, 20 showed a diffuse hypoechogenicity of the thyroid gland to
ultrasound evaluation, significantly higher than in BBD (7/25: 28%) (P = 0.03). Of the 20 BC patients who showed a
hypoechogenic pattern of thyroid gland, 10 (50%) were associated with antithyroid antibodies positivity (TAb).
This finding was present in two of seven BBD (28.57%) (P < 0.0001). Only two controls showed focal
hypoechogenicity of the thyroid gland. Generally, 24 out of 36 (66.7%) of BC and 9 out of 25 (36%) of BBD (P = 0.02)
had signs of thyroid autoimmunity consistent with the hypoechogenic pattern of thyroid gland associated or not
with TAb; 2 out of 36 (5.55%) of BC and 1 out of 25 (4%) of BBD patients had autoimmune hypothyroidism and no
hypothyroidism was found in controls.
CONCLUSIONS: The results of this study confirm the strong relation between thyroid autoimmunity and BC. This
finding is independent of stressful events represented by surgery or anaesthetic procedures. The present data
call attention to the usefulness of screening for autoimmune thyroid disorders in patients with nodular breast
disease selected for surgery.
Association between breast cancer and autoimmune thyroid disorders: no increase of lymphocytic infiltrates in
breast malignant tissues.
Fierabracci P, Pinchera A, Campani D, Pollina LE, Giustarini E, Giani C.
J Endocrinol Invest. 2006 Mar;29(3):248-51.
[abstract only]
An association between thyroid autoimmunity and breast cancer (BC) has been consistently reported, but the
cause of this association is still unknown. The role of lymphocytic infiltration (LI) in breast tumorigenesis is
controversial and several data suggest that in BC an increase of lymphoid cell infiltrates or a dysfunctional local
immune response may be detected very early during tumor development. Chronic autoimmune thyroiditis is
characterized by different degrees of LI in thyroid gland and BC cells share some antigenic properties similar to
those detected in thyroid tissue, such as sodium iodide symporter (NIS) and peroxidase activity.
The aim of this study was to evaluate the frequency and amount of LI in malignant and in normal peritumoral
breast tissues, as expression of autoimmune morphological changes, in a group of BC patients with thyroid
autoimmunity. We suppose that an increased LI in breast tissues of this group of patients may help explain the
association between BC and thyroid autoimmunity.
The study group included 26 BC patients with thyroperoxidase antibodies positivity (TPOAb+), 14 of them (53.8%)
with Hashimoto's thyroiditis (HT), and 30 BC patients with no evidence of thyroid autoimmune disorders.
Malignant and surrounding normal breast tissues were assessed for LI. The amount of LI was scored as very
scanty or scanty (LI S) and moderate or marked (LI M), independently by two expert pathologists.
LI S was detected in 19/26 (73.1%) BC tissues from patients with TPOAb positivity and LI M in 7 (26.9%). All BC
patients with HT had LI S. LI S was detected in 25/30 (83%) and LI M in 5/30 (17%) of BC tissue from patients with
no thyroid autoimmunity. The difference in the amount of LI of BC tissues in patient with or without autoimmune
thyroid disorders was not significant. The LI was generally absent or very scanty in remote breast tissue in all
cases.
In conclusion, in breast malignancies the presence of humoral and/or clinical evidence of thyroid autoimmunity is
not associated to autoimmune morphological changes of cancer and peritumoral normal tissue. The LI does not
seem to have any role in tumorigenesis in patients with BC and thyroid autoimmunity.
Absence of interference of serum IgGs from patients with breast cancer and thyroid autoimmunity on the
function of human iodide symporter gene stably transfected in CHO cells.
Fierabracci P, Pinchera A, Tonacchera M, Agretti P, De Marco G, Albertini S, Conforti G, Seregni E, Agresti R,
Grasso L, Giani C.
J Endocrinol Invest. 2004 Oct;27(9):862-5.
[abstract only]
The cause of the association between breast cancer (BC) and thyroid autoimmunity is still unknown. Na+/I-
symporter (NIS) is highly expressed in BC cells, and previous studies demonstrated that iodine content in BC is
lower than in remote normal breast tissue, suggesting a disorder of iodide uptake in BC.
In this study, we evaluated the presence of putative serum autoantibodies able to block the function of NIS in BC
patients with thyroid autoimmunity. IgGs were obtained from: a) 11 patients with BC and high antithyroglobulin
(TgAb) and antithyroperoxidase (TPOAb) autoantibodies serum concentration; b) 34 patients with Hashimoto's
thyroiditis (HT) (1 was euthyroid, 4 had subclinical hypothyroidism and 29 were overtly hypothyroid); c) 15 control
subjects. The biological activity of NIS was studied using a chinese hamster ovary (CHO) cell line stably
expressing NIS (NIS-CHO). The course of iodide accumulation in NIS-CHO was studied after addition of Na125 I in
culture medium.
The accumulation of iodide linearly increased between 2 and 10 min, reaching a plateau at 45 min. The
preincubation of NIS-CHO with IgGs purified from sera of BC with the highest levels of TPOAb and TgAb caused
an inhibition of iodine uptake of no more than 5%. Similar results were obtained using IgGs purified from patients
with HT and control subjects.
Our data showed no interference of autoantibodies on iodine uptake in patients with BC and thyroid autoimmunity
and the very low percentage of inhibition of iodine uptake cannot explain the lower content of iodine in BC tissue.
Relationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast
malignancy.
Giani C, Fierabracci P, Bonacci R, Gigliotti A, Campani D, De Negri F, Cecchetti D, Martino E, Pinchera A.
J Clin Endocrinol Metab. 1996 Mar;81(3):990-4.
The relationship between thyroid dysfunction and breast cancer (BC) is debated. To clarify this controversial
issue, a prospective study on thyroid function in BC was performed.
The prevalence of thyroid disease was examined in 102 consecutive BC patients with ductal infiltrating
carcinoma after surgery and before starting any chemohormonal or x-ray therapy and in 100 age-matched
control healthy women living in the same borderline iodine-sufficient geographic area. All subjects were
submitted to clinical ultrasound thyroid evaluation and serum free T4, free T3, TSH, thyroperoxidase antibody,
and thyroglobulin antibody determination. Fine needle aspiration was performed in all thyroid nodules. Estrogen
and progesterone receptors (ER and PR, respectively) were assayed in 92 and 55 BC specimens, respectively.
The overall prevalence of thyroid disease was 47 in 102 (46%) in BC patients and 14 in 100 (14%) in controls (P <
0.0001). The prevalence of nontoxic goiter was 27.4% in BC patients and 11% in controls (P = 0.003). Hashimoto's
thyroiditis was found in 13.7% of BC patients and in only 2% of the controls (P < 0.005). Other thyroid disorders
found in the BC group included 2 cases of Graves' disease, 2 of thyroid carcinoma, and 1 of subacute thyroiditis,
whereas in the control group only 1 case of Graves' disease and none of the other disorders were found. Mean
free T3, free T4, and TSH concentrations showed no difference between BC patients and controls. The
prevalence of thyroperoxidase antibody was higher in BC patients than in controls (23.5% vs. 8%; P < 0.005),
whereas the prevalence of thyroglobulin antibody was not different. In BC patients the presence of thyroid
antibodies was more frequently associated with clinically detectable autoimmune thyroiditis (14 of 26, 51.8%; P =
0.03) and was more common in the younger group. The positivity of ER was found in 51 of 92 (55.43%) and that of
PR was found in 26 of 55 (47.27%) BC specimens. No relationship was found among ER, PR status, and the
presence of serum thyroid antibodies.
In conclusion, 1) the present study provides evidence that the overall prevalence of thyroid disorders is
increased in patients with breast cancer, and 2) thyroid autoimmune disorders, especially Hashimoto's
thyroiditis, account to a large extent for the increased prevalence of thyroid disease in patients with breast
cancer. This feature is independent from the ER and PR status of the primary tumor. The present findings call
attention to the usefulness of screening for thyroid disease in any patient with breast cancer.
HARTMANN
Benign breast disease and the risk of breast cancer.
Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankratz VS,
Hillman DW, Suman VJ, Johnson J, Blake C, Tlsty T, Vachon CM, Melton LJ 3rd, Visscher DW.
N Engl J Med. 2005 Jul 21;353(3):229-37.
BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We studied a large group of
women with benign breast disease to obtain reliable estimates of this risk.
METHODS: We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic
between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To
estimate relative risks, we compared the number of observed breast cancers with the number expected on the
basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry.
RESULTS: We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative
lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4
percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56
(95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy.
The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with
a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of
1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history
of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No
increased risk was found among women with no family history and nonproliferative findings. In the first 10 years
after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia.
CONCLUSIONS: Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic
classification of a benign breast lesion and a family history of breast cancer.
HOWENSTINE
Thyroid Hormone Therapy Appears to Cause Breast Cancer
Dr. James Howenstine, MD.
NewsWithViews.com July 27, 2006
When humans lack iodine the thyroid gland enlarges (goiter), nodules appear in the thyroid gland and over a
period of time cancer may appear in a thyroid nodule. Conventional medicine treats thyroid gland enlargement
with thyroid hormone without considering the possibility that the hypothyroidism and goiter may be due to lack of
iodine. This failure to diagnose and treat iodine deficiency can lead to an increased risk of breast cancer and the
longer the diagnosis is missed the greater the chance that breast cancer will occur. Women taking thyroid
hormone appear to be twice (12.1%) as likely to develop breast cancer as women not using thyroid hormone (6..
2%). Women who had taken thyroid hormone for 15 years had a 19.5% incidence of breast cancer whereas
women who have only taken thyroid hormone for 5 years had only a 10% incidence of breast cancer.
IWAMOTO
The Mechanistic Role of Iodine in Breast Carcinogenesis
Iwamoto KS
US Army Medical Research and Materiel Command, October 2005.
There is both considerable interest and ignorance in the possible role of iodine in the etiology and prognosis of
breast cancer. This project is the first step in elucidating a mechanistic role for iodine in breast carcinogenesis.
The data that we have been able to generate to date suggest that our hypothesis is correct; namely, using
transgenic human breast cancer cells (MCF7) overexpressing the sodium/iodide symporter (NIS) and/or
lactoperoxidase (LPO), we have shown that NIS facilitates death or survival pathways following irradiation, a
known human breast carcinogen, depending on the presence or absence of iodine, respectively, and that this
switching can be modulated by the cell's ability to organify and stabilize the iodine via LPO. Further, we have
shown that expression of both NIS and LPO will radiosensitize the MCF7 cells while NIS alone will make them
radioresistant and more aggressive. These data agree with observations made by others demonstrating that
iodine deficiency is correlated with increased breast cancer incidence, and that a large percentage of human
breast cancers overexpress NIS. Additionally, the fact that NIS and LPO are most active in the mammary glands
during late pregnancy and lactation may explain the well established observation that early and frequent parity
and long lactation history reduce the risk for breast cancer development. We are confident that the data from the
experiments currently in progress should help to strengthen our already existing results. Clarification of these
issues should foster future studies not only in breast cancer diagnosis and therapy but also in prevention
through conscious changes in diet and environment.
KAPDI
Breast cancer. Relationship to thyroid supplements for hypothyroidism.
Kapdi CC, Wolfe JN.
JAMA. 1976 Sep 6;236(10):1124-7.
This study was undertaken to determine the relationship between thyroid supplements and breast cancer. The
incidence of breast cancer among the patients who received thyroid supplements was 12.13%, while in the
control group it was 6.2%. The incidence rate of breast cancer was 10%, 9.42%, and 19.48% among patients who
received thyroid supplements for one to five, 5 to 15, and for more than 15 years, respectively. The incidence of
breast cancer among nulliparous women who received thyroid supplements was 33%, while in the nulliparous
women without thyroid supplements the incidence was only 9.25%. Even in a specific age group, the incidence
rate of breast cancer was higher among patients receiving thyroid supplements, when compared to the control
patients in the same age group.
KESSLER
Aqueous Iodine Equilibria in Mammalian Iodination Reactions
Kessler J, Hooge D
Thyroid, Jan 2007, Vol. 17, No. 1 : 19 -24
Regulatory activity has been demonstrated in two classes of iodinated organic species: thyroid hormones (T3
and T4) and iodinated lipids (ILs), e.g. 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid. The formation of iodinated
biomolecules requires iodide oxidation. In mammals iodide oxidation is one of several peroxidase-mediated
reactions that serve to reduce hydrogen peroxide. I2 is one of several reaction products formed by mammalian
peroxidases during iodide oxidation. I2 forms HOI in an aqueous environment which also has the capacity to
iodinate organic species. This manuscript examines the potential relationship between the two classes of
known mammalian iodinating species. A model describing iodination pathways for organic species in mammals
is advanced. The model predicts the formation of ILs under normal dietary intake of iodine. The model was
challenged by characterizing the lipids of hogs maintained on a diet containing normal levels of iodine. Iodinated
lipids were found to be present in the fatty acids extracted from the thyroid of these hogs.
The Effect of Supraphysiologic Levels of Iodine on Patients with Cyclic Mastalgia
Kessler JH.
Breast J. 2004 Jul-Aug;10(4):328-36.
A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted with 111 otherwise
healthy euthyroid women with a history of breast pain.... A statistically significant improvement (p < 0.01)
associated with dose was observed in the Lewin overall pain scale for all treated groups compared to placebo.
Reductions in all three physician assessments were observed in patients after 5 months of therapy in the 3.0
mg/day (7/28; 25%) and 6.0 mg/day (15/27; 18.5%) treatment groups, but not the 1.5 mg/day or placebo group.
Patients recorded statistically significant decreases in pain by month 3 in the 3.0 and 6.0 mg/day treatment
groups, but not the 1.5 mg/day or placebo group; more than 50% of the 6.0 mg/day treatment group recorded a
clinically significant reduction in overall pain. All doses were associated with an acceptable safety profile. No
dose-related increase in any adverse event was observed.
IoGen - Breast Pain Clinical Research Trial
Symbollon is enrolling patients in a national multi-center, placebo-controlled, double-blinded, randomized Phase
III clinical trial for the treatment of moderate or severe breast pain associated with fibrocystic breast disease.
The trial drug, IoGen, may help relieve breast pain. The study has been registered with FDA under the Protocol
Registration System at ClinicalTrials.gov.
Symbollon provides update on IoGen Phase III Pain Study
Symbollon
August 9, 2006
It anticipates closing the enrollment of its IoGen™ Phase III pivotal pain study by yearend. The ongoing IoGen
study has over 25 active sites across the United States. Symbollon is planning to conduct a comprehensive
advertising campaign during the remainder of 2006 to assist these sites in recruiting subjects for the study by
yearend.
Research calls for use of molecular iodine to treat breast cancer
Symbollon
October 31, 2006
Symbollon Pharmaceuticals, Inc. (OTCBB: SYMBA) today provided a review of recent independent scientific
publications focused on the possible use of molecular iodine, the active agent in Symbollon’s drug, IoGen™, to
treat breast cancer. The results of such research identify molecular iodine as a possible treatment for breast
cancer. This research recommends the initiation of human clinical trials testing molecular iodine as an adjuvant
therapy for breast cancer.
Iodine's Mechanism of Action (link to paper is no longer available on the internet)
Kessler J
The relationship between iodine intake, thyroid hormones and breast cancer has engaged the interest of
clinicians for well over 50 years. Within the past thirty years diverse experimental observations examining (1) the
autoregulatory mechanism in the thyroid, (2) the dynamic control of pituitary derived prolactin in patients with
fibrocystic breast disease and (2) aqueous iodine chemistry, have provided a mechanistic basis that for the
variety of epidemiological, non-clinical and clinical observations related to iodine intake and mammary tissue.
The thyroid needs a mechanism to protect itself from chronic exposure to high levels of iodine. Observations
from a variety of different laboratories indicate that the enzyme peroxidase catalyzes the formation of iodinated
polyunsaturated fatty acids, such as arachidonic acid and docosahexaenoic acids, instead of tyrosine at
elevated concentrations of iodide. Several of the iodinated lipids formed by peroxidase have been shown to
exhibit a broad antiproliferative effect. Iodolactones have been shown to inhibit the production of inositol
phosphates induced by epidermal growth factor (EGF); the hydrogen peroxide production by NADPH oxidases;
and adenylyl cyclase. Several leading researchers in this field believe that the antiproliferative activity of
iodolactones and iodoaldehyes mediate thyroid autoregulation. These iodolipids should be able to be formed in
other tissues of the body.
The formation of these iodinated lipids is reasonable based upon the enzymology of peroxidase and aqueous
iodine chemistry. The mechanism of the enzyme peroxidase has been studied for close to 100 years. Between
1940 and 1990 many teams of expert enzymologists around the world attempted to identify how peroxidase
catalyzes the formation of thyroid hormones. Despite thousands of published studies we cannot identify a
discrete set of experiments that unequivocally identify the mechanistic pathway for thyroid hormone synthesis.
An overlooked factor that probably contributes to this difficulty is the characteristics of the oxidized iodide. Hatch
developed the first complete set of equations that describe the behavior of the I2 species in an aqueous
environment. In the 1980s Gottardi developed a computer program that solves the nonlinear equations
describing this equilibrium. It is clear from Gottardi's studies that oxidized iodide species do not behave in a
linear manner. That is, the reaction product(s) from the oxidation of iodide by peroxidase can vary depending
upon the concentration of the reactants. It is not, therefore, unreasonable that at physiologic levels of iodide
tyrosine is iodinated while at elevated levels other iodine species, like I2, are formed. Peroxidase mediated
formation of iodinated lipids at elevated iodide concentrations is reasonable from the perspective of iodine
chemist since molecular iodine (I2) formation could be expected under these conditions. In fact, Symbollon has
used this reaction as the basis of the first product developed by the company
The requirements for the formation of iodinated lipids are (1) a peroxidase, (2) an elevated concentration of
iodide and (3) hydrogen peroxide. These conditions can be met in the mammary gland, oviduct and uterus.
Symbollon Patents for Breast Iodine
6248335 Stabilized oral pharmaceutical composition containing iodide and iodate and...
- A stabilized solid oral pharmaceutical composition comprised of iodide and iodate as the active agents in
the presence of one or more pharmaceutical excipients and a method for preparing these stabilized
compositions. 2001-06-19
- The invention is a method of administering therapeutic iodine for treating a disorder in a mammal. The
invention comprises a step of feeding said mammal an effective amount of an oxidant for an iodine
species and an iodine reductant which will cause oxidation-reduction reactions upon contact with...
1999-03-23
KOGAI
Enhancement of sodium/iodide symporter expression in thyroid and breast cancer.
Kogai T, Taki K, Brent GA.
Endocr Relat Cancer. 2006 Sep;13(3):797-826.
The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA
and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is
usually reduced resulting in the characteristic finding of a 'cold' or non-functioning lesion on a radioiodine image.
Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated
thyroid cancer to utilize beta-emitting radioactive iodide for the treatment of residual and metastatic disease.
Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human
thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma
membrane, increasing radioiodide uptake. Approximately 10-20% differentiated thyroid cancers, however, do not
express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis.
Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal
promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer
specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various
nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A
wide range of 'differentiation' agents have been utilized to stimulate NIS expression in thyroid and breast cancer
using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to
stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene
regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in
thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor
differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in 'scan-negative'
thyroid cancer and some breast cancer.
Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse
breast cancer models.
Kogai T, Kanamoto Y, Che LH, Taki K, Moatamed F, Schultz JJ, Brent GA.
Cancer Res. 2004 Jan 1;64(1):415-22.
Lactating breast tissue and some breast cancers express the sodium/iodide symporter (NIS) and concentrate
iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and iodide
accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we
investigated the in vivo efficacy and specificity of tRA-stimulated iodide accumulation in mouse breast cancer
models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide
accumulation in the xenograft tumors was markedly increased, approximately 15-fold greater than levels
without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not
significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors
was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced
in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These
data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term
systemic retinoic acid, followed by radioiodide administration, is a potential tool in the diagnosis and treatment of
some differentiated breast cancer.
Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast
cancer cell line.
Kogai T, Schultz JJ, Johnson LS, Huang M, Brent GA.,
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8519-24.
The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be
active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells,
an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment
stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold above baseline.
Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by
retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein (
approximately 68 kDa). tRA stimulated NIS gene transcription approximately 4-fold, as shown by nuclear run-on
assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer
cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7
cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide
retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with (131)I after tRA
stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast
cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis
and treatment of some differentiated breast cancers.
LIM, MOON
Enhanced Expression of Adenovirus-Mediated Sodium Iodide Symporter Gene in MCF-7 Breast Cancer Cells with
Retinoic Acid Treatment.
Lim SJ, Paeng JC, Kim SJ, Kim SY, Lee H, Moon DH.
J Nucl Med. 2007 Mar;48(3):398-404.
[abstract only]
Increased expression of the sodium iodide symporter (NIS) is required for effective radioiodine treatment and
reporter gene imaging of breast cancer. We investigated the effect of retinoic acid on adenovirus-mediated
expression of the human NIS gene in the MCF-7 breast cancer cell line.
METHODS: The MCF-7 cell line was infected with recombinant adenovirus carrying the human NIS gene (Rad-NIS).
Levels of NIS messenger RNA (mRNA) and protein expression and radioiodine ((125)I) uptake were measured to
evaluate adenovirus-mediated NIS gene expression in wild-type and Rad-NIS-infected MCF-7 cells after treatment
with all-trans-retinoic acid (ATRA; 10(-8)-10(-6) mol/L).
RESULTS: The transduction efficiency of adenovirus in MCF-7 cells at a multiplicity of infection (MOI) of 50 was
>60%. After incubation with 10(-6) mol/L ATRA, the mRNA level in Rad-NIS-infected MCF-7 cells increased to 118.5
times that of wild-type MCF-7 cells, whereas the mRNA level in wild-type MCF-7 cells showed only a 2.1-fold
increase. Western blot, immunocytochemical staining, and flow cytometry analyses showed that NIS protein
expression in MCF-7 cells infected with Rad-NIS increased after ATRA treatment. With ATRA treatment, the
amount of (125)I uptake increased in a dose-dependent manner (P < 0.001). The (125)I uptake in wild-type MCF-7
cells increased 3.1-, 5.5-, and 7.6-fold with treatment with 10(-8), 10(-7), and 10(-6) mol/L ATRA, respectively. Rad-
NIS-infected cells showed a 4.0-fold increase in (125)I uptake. Treatment of Rad-NIS-infected cells with 10(-8), 10
(-7), and 10(-6) mol/L ATRA increased (125)I uptake by 4.9-, 8.2-, and 27.6-fold, respectively, compared with wild-
type MCF-7 cells. The level of NIS expression in Rad-NIS-infected MCF-7 cells treated with 10(-6) mol/L ATRA
(245.0 +/- 13.7 pmol/10(6) cells) was much greater than the sum of the expression levels seen in ATRA-treated
wild-type cells and Rad-NIS-infected wild-type cells.
CONCLUSION: Retinoic acid increases adenovirus-mediated NIS expression in MCF-7 cells. Our results indicate
that improved efficiency of NIS gene therapy or reporter imaging in breast cancer may be possible with retinoic
acid treatment.
NATARAJAN
Role of lipoxygenases in breast cancer.
Natarajan R, Nadler J.
Front Biosci. 1998 Jun 8;3:E81-8. Review.
[abstract only]
The interaction of growth factors such as epidermal growth factor (EGF) with their receptors on breast cancer
cells can lead to the hydrolysis of phospholipids and release of fatty acids such as arachidonic acid which can
be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate
oncogenes and have mitogenic and chemotactic effects. The 12-LO product, 12-hydroxyeicosatetraenoic acid (12
(S)HETE), has been shown to play a key role in mediating several steps of the process of hematogenous
metastasis and tumor cell adhesion. 12-LO can also be activated by several growth factors and inflammatory
cytokines. A growing body of evidence suggests that specific metabolites of arachidonic and/or linoleic acid
serve as central elements in signal pathways necessary for cell mitogenesis as induced by growth factors or
oncogenic transformation. This review examines the role of LOs in breast cancer. The growth of breast cancer
cells has been shown to increased by certain LO products and, LO pathway inhibitors could block the growth of
some breast cancer cells. 12-LO activity and expression was increased in breast cancer tissues relative to the
uninvolved normal tissue, and also in cultured breast cancer cells relative to normal breast cells. Treatment of
the breast cancer cell line, MCF-7 cells, with epidermal growth factor (EGF), led to significant increases in 12-LO
activity and expression. Thus, activation of the 12-LO pathway may play a key role in basal and EGF-induced
breast cancer cell growth.
Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor.
Natarajan R, Esworthy R, Bai W, Gu JL, Wilczynski S, Nadler J.
J Clin Endocrinol Metab. 1997 Jun;82(6):1790-8.
The interaction of growth factors, such as epidermal growth factor (EGF) with their receptors, on breast cancer
cells can lead to the hydrolysis of phospholipids and release of fatty acids, such as arachidonic acid, which can
be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate
oncogenes and have mitogenic and chemotactic effects. In this study, we have evaluated the regulation of 12-LO
activity and expression in breast cancer cells and tissues. Leukocyte-type 12-LO messenger RNA (mRNA)
expression was studied by a specific RT-PCR method in matched, normal, uninvolved and cancer-involved breast
tissue RNA samples from six patients. In each of these six patients, the cancer-involved section showed a much
higher level of 12-LO mRNA than the corresponding normal section. 12-LO mRNA levels also were greater in two
breast cancer cell lines, MCF-7 and COH-BR1, compared with the nontumorigenic breast epithelial cell line, MCF-
10F. The growth of the MCF-7 cells was significantly inhibited by two specific LO blockers but not by a
cyclooxygenase blocker. Treatment of serum-starved MCF-7 cells with EGF for 4 h led to a dose-dependent
increase in the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid. EGF treatment also increased
the levels of the leukocyte-type 12-LO protein expression at 24 h. These results suggest that activation of the 12-
LO pathway may play a key role in basal and EGF-induced breast cancer cell growth.
PARK
Sonographic detection of thyroid cancer in breast cancer patients.
Park JS, Oh KK, Kim EK, Son EJ, Chang HS, Hong SW, Moon HJ, Kwack KS.
Yonsei Med J. 2007 Feb 28;48(1):63-8.
[abstract only]
The purpose of our study was to analyze the incidence of incidental thyroid cancers which were detected by
simultaneous sonographic examination of breast and thyroid glands. Between January 2001 and March 2004,
518 patients were diagnosed with breast cancer after modified radical mastectomy (n=369) or breast
conserving surgery (n=149). We screened thyroid glands when we examined breast for diagnosis and follow-up
after surgery. If we found the sonographic finding of suspicious for malignancy in thyroid, we immediately
performed ultrasound-guided fine needle aspiration biopsy (FNAB). Forty-two cases showed suspicious
sonographic findings and of those, 18 cases (42.9%) were determined to have suspicious malignant cytology by
ultrasound guided FNAB. Among 518 breast cancers, total 13 cases (2.5%) were diagnosed with papillary
carcinoma after thyroidectomy. The mean longest diameter of the thyroid masses was 9.9mm (range 1-30mm).
Six cases (6/13, 46.2%) were diagnosed as simultaneous breast and thyroid cancers, and the rest of the thyroid
cancers were detected after 6 to 33 months (mean 16.5 months) after surgery. In conclusion, the patients with
breast cancer had a high incidence (2.5%) of thyroid cancer. Sonographic screening is useful for the early
detection of thyroid cancer.
PERRON
Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues.
Perron B, Rodriguez AM, Leblanc G, Pourcher T.
J Endocrinol. 2001 Jul;170(1):185-96.
Iodide concentration in milk by mammals is a necessary step for thyroid hormone synthesis by the newborn.
With the purpose of using the mouse as an animal model to analyse the role of the sodium iodide symporter (NIS)
in iodide transport and its regulation in the mammary gland, mouse NIS (mNIS) cDNA was isolated from lactating
mice. The cloned sequence shows an open reading frame of 1854 nucleotides encoding a protein of 618 amino
acids highly homologous to the rat and human NIS (95% and 81% identity respectively). Expression of mNIS in
cultured mammalian cells induced cellular iodide accumulation. This iodide uptake process is sodium dependent
and inhibited by thiocyanate and perchlorate. Tissue distribution analysis revealed that mNIS mRNAs are
predominantly expressed in thyroid, stomach and in the lactating mammary gland and are present to a lower
extent in several other tissues. Our data show for the first time that the level of mNIS mRNA is upregulated in the
mammary gland during lactation.
RILLEMA
Pendrin transporter carries out iodide uptake into MCF-7 human mammary cancer cells.
Rillema JA, Hill MA.
Exp Biol Med (Maywood). 2003 Oct;228(9):1078-82.
Previous studies have shown that iodide is actively taken up into mammary alveolar epithelial cells and secreted into
milk. In the present studies we demonstrate that 125I also accumulates in MCF-7 cells against a concentration
gradient; distribution ratios of greater than 30 were achieved. Iodide uptake into MCF-7 cells is transient, with peak
accumulations occurring in about 5 min. The iodide is rapidly metabolized, probably to iodine, and it then exits the
cells. The iodide transporter identified in MCF-7 cells is pendrin. DIDS, a nonspecific inhibitor of anion exchange,
inhibits iodide uptake. Iodide uptake is impaired at reduced temperature, but is not dependent on sodium. Inhibitors
of the sodium-iodide symporter (NIS) as well as ouabain did not affect the extent of iodide uptake. The pendrin
transporter but not NIS was identified via western blotting techniques. Pendrin appears to be the primary iodide
transporter in the MCF-7 cell line stocks that were employed for these studies.
Prolactin regulation of the pendrin-iodide transporter in the mammary gland.
Rillema JA, Hill MA.
Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E25-8. Epub 2002 Sep 11.
Iodide is an essential constituent of milk that is present in concentrations more than an order of magnitude higher
than in the maternal plasma. Earlier, a sodium-iodide symporter was identified in the mammary gland; this
transporter is presumed to take iodide from the maternal plasma into the alveolar epithelial cells of the mammary
gland. We now report the existence of a second iodide transporter, pendrin, which is also essential for iodide
accumulation in milk. Via Western blotting methods, high levels of the transporter were detected in lactating tissues;
lesser amounts were found in tissues from midpregnant and virgin mice. Prolactin, at physiological concentrations,
stimulated the expression of the pendrin transporter in cultured mammary tissues taken from 12- to 14-day-pregnant
mice. The prolactin effect on iodide uptake into cultured mammary tissues was abolished by pendrin transport
inhibitors, including DIDS, furosemide, and probenecid. These studies suggest that the prolactin stimulation of
pendrin activity is an essential element in the prolactin stimulation of iodide uptake into milk.