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Iodine Research

Resource Network of The Iodine Movement


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                            Iodine and the Body

Breast

ESKIN-GHENT
Iodine Alters Gene Expression in the MCF7 Breast Cancer Cell Line: Evidence for an Anti-Estrogen Effect of
Iodine
Stoddard, FR, Brooks, AD, Eskin, BA and Johannes, GJ

The protective effects of iodine on breast cancer have been postulated from epidemiologic evidence and
described in animal models. The molecular mechanisms responsible have not been identified but laboratory
evidence suggests that iodine may inhibit cancer promotion through modulation of the estrogen pathway. To
elucidate the role of iodine in breast cancer, the effect of Lugol's iodine solution (5% I2, 10% KI) on gene
expression was analyzed in the estrogen responsive MCF-7 breast cancer cell line. Microarray analysis identified
29 genes that were up-regulated and 14 genes that were down-regulated in response to iodine/iodide treatment.
The altered genes included several involved in hormone metabolism as well as genes involved in the regulation
of cell cycle progression, growth and differentiation. Quantitative RT-PCR confirmed the array data demonstrating
that iodine/iodide treatment increased the mRNA levels of several genes involved in estrogen metabolism
(CYP1A1, CYP1B1, and AKR1C1) while decreasing the levels of the estrogen responsive genes TFF1 and
WISP2. This report presents the results of the first gene array profiling of the response of a breast cancer cell line
to iodine treatment. In addition to elucidating our understanding of the effects of iodine/iodide on breast cancer,
this work suggests that iodine/iodide may be useful as an adjuvant therapy in the pharmacologic manipulation of
the estrogen pathway in women with breast cancer.

Iodine alters gene expression profile in the MCF-7 breast cancer cell line
Stoddard FR, Shah K, Johannes G, Eskin B, Brooks A
Thyroid Vol 16(9) Sept 2006 page 894
[poster abstract]

This study provides the first report of the altered gene expression profile which results from iodine treatment of a
breast cancer cell line.  Several biological pathways involved in cancer growth and development were identified.  
These changes are possibly responsible for iodine's inhibition of breast cancer promotion.

Identification of Breast Cancer by Differences in Urinary Iodine
Eskin BA, Anjum W, Abraham GE, Stoddard F, Prestrud AA,  Brooks AD
Proc Amer Assoc Cancer Res 2005:46
[abstract only]

These preliminary results are the first to show a significant decrease in iodine excretion in women with
malignant breast diseases. Basic studies have shown a significantly lower iodine availability in breast tissue
harboring malignancy. These data indicate that iodine plays a role in breast cell differentiation. These provocative
findings imply potential diagnostic and therapeutic capabilities in the iodine pathway.

The Effect of Iodine Replacement on Lactoperoxidase in Mammary Gland Dysplasia
Eskin, Brooks, & Connolly
Abstract Submission, 2003.

An iodine pathway has been described for the mammary glands (MG) and has a major effect on secretory and
anatomical changes.  This pathway is most evident during gestation, lactation and neoplasia, and is present, but
less prominent in inactive MG.  In neoplastic breast tissues, peroxidase activity (PA) is inversely related to
estrogen receptor alpha (ER) concentration and tumor size in induced rat mammary carcinomas.  In the iodine
pathway of MG, PA may restrict estrogen action.  This, iodine deficiency of the breast may reduce peroxidase
protection by increasing ER concentrations.

OBJECTIVE.  The present study is designed to measure PA in iodine deficient (ID) and ID+ iodine- or iodide-
treated rats given estrogen supplementation.  The program includes replacement with iodine and iodide as well
as tamoxifen therapy as a control....

CONCLUSIONS.  This preliminary study indicates again that iodine deficiency results in FC [fibrocystic changes]
or dysplastic changes in MG.  Peroxidase levels are reduced in iodine deficiency which appears to be
responsible for enhanced ER activity.  Iodine replacement requires less peroxidase than iodide to promote the
oxidation for the formation of iodoprotein.  The antiestrogen, tamoxifen, acts directly on estrogen metabolism.  
Thus, this preliminary study proposes how iodine metabolism is associated with estrogen activity that results in
dysplasia and neoplasia in the MG.

US Patent 5,589,198.  Treatment of Iodine Deficiency Diseases
Eskin BA, Ghent RA
December 31, 1996

This invention relates to a composition for use in the treatment or prevention of iodine deficiency diseases or
disorders such as fibrocystic dysplasia of the breast, breast cancer, endometriosis, ovarian cysts and
premenstrual syndrome.  More particularly, this invention relates to a composition for the treatment or prevention
of iodine deficiency diseases or disorders, the composition comprising elemental iodine (I.sub.2) which may
also be referred to as metallic iodine or iodine metal.  The elemental iodine can be used with any
pharmaceutically acceptable carrier.

Eskin Patents
5389385 Treatment of iodine deficiency diseases
    This invention relates to a composition for use in the treatment of iodine deficiency diseases such as
    fibrocystic dysplasia of the breast, breast cancer, endometriosis and premenstrual syndrome. The
    composition may also be used for the prophylaxis of breast cancer. More particularly, this...        1995-02-
    14
4816255 Treatment of iodine deficiency breast syndrome
    This invention relates to a composition for use in the treatment of fibrocystic dysplasia which may reduce
    or dissipate cyst formation in the female breast and alleviate the pain and discomfort associated with this
    disease. More particularly, this invention relates to a composition for the...        1989-03-28
5250304 Treatment of iodine deficiency diseases
    This invention relates to a composition for use in the treatment of iodine deficiency diseases such as
    fibrocystic dysplasia of the breast, breast cancer, endometriosis and premenstrual syndrome. The
    composition may also be used for the prophylaxis of breast cancer. More particularly, this...        0001-01-
    01
6019970 Treatment of iodine deficiency diseases
    This invention relates to a composition for use in the treatment or prevention of iodine deficiency
    diseases or disorders such as fibrocystic dysplasia of the breast, breast cancer, endometriosis, ovarian
    cysts and premenstrual syndrome. More particularly, this invention relates to a composition...        2000-
    02-01

Diatomic Iodine Treatment for Fibrocystic Disease
Low DE, Ghent WR, Hill LD
[Submitted to the FDA] 1995:1-38.   

(The sponsor, Mimetix, Inc., submitted this report to the FDA seeking its approval to do a larger clinical trial.  The
FDA refused to approve it.)
 

This prospective, double-blind, randomized, placebo-controlled investigation in FCD patients was designed to
compare aqueous diatomic iodine to placebo for the treatment of pain and the fibrotic and cystic components of
FCD of the breast.  The seven-month treatment period involved an initial dose of 10ml/day (1.95 mg iodine/day),
which could be doubled if no clinical effect was observed.

Results:... The iodine-treated group Total Breast Examination Score declined from a mean of 37.3 (at Baseline)
to a mean of 13.5 (at Month 7), showing a mean change of -23.9; the placebo-treated group score declined from
a mean of 35.3 (at Baseline) to a mean of 32.7 (at Month 7), showing a mean change of -2.6.  (p < 0.001)... No
serious Adverse Event was reported.... There was no evidence of any influence of treatment with diatomic iodine
on Heart Rate, Body Weight, or Thyroid Function."  [Note:  The study includes data on T3 Uptake, Total T4 and
TSH, including tables.]

Different tissue responses for iodine and iodide in rat thyroid and mammary glands.
Eskin BA, Grotkowski CE, Connolly CP, Ghent WR.
Biol Trace Elem Res. 1995 Jul;49(1):9-19.

This research describes the effects of short-term elemental iodine (I2) and iodide (I-) replacement on thyroid
glands and mammary glands of iodine-deficient (ID) Sprague-Dawley female rats. Iodine deficiency causes
atypical tissue and physiologic changes in both glands. Tissue histopathology and the endocrine metabolic
parameters, such as serum TT4, tissue and body weights, and vaginal smears, are compared. A moderate
reduction in thyroid size from the ID control (IDC) was noted with both I- and I2, whereas serum total thyroxine
approached the normal control with both I- and I2, but was lower in IDC. Thyroid gland IDC hyperplasia was
reduced modestly with I2, but eliminated with I-. Lobular hyperplasia of the mammary glands decreased with I2
and increased with I- when compared with the IDC; extraductal secretions remained the same as IDC with I2, but
increased with I-; and periductal fibrosis was markedly reduced with I2, but remained severe with I-. Thus, orally
administered I2 or I- in trace doses with similar iodine availability caused different histopathological and
endocrine patterns in thyroid and mammary glands of ID rats. The significance of this is that replacement therapy
with various forms of iodine are tissue-specific.

Iodine replacement in fibrocystic disease of the breast.
Ghent WR, Eskin BA, Low DA, Hill LP
Can J Surg. 1993 Oct;36(5):453-60.

OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine replacement
therapy. DESIGN: Review of three clinical studies beginning in 1975: an uncontrolled study with sodium iodide
and protein-bound iodide; a prospective, control, crossover study from iodide to molecular iodine; and a
prospective, control, double-blind study with molecular iodine.

SETTING: University affiliated breast-treatment clinics. PATIENTS: Study 1: 233 volunteers received sodium
iodide for 2 years and 588 received protein-bound iodide for 5 years. Study 2: the treatment of 145 patients from
study 1 treated with protein-bound iodide for several months who still had symptoms was switched to molecular
iodine 0.08 mg/kg; 108 volunteers were treated initially with molecular iodine. Study 3: 23 patients received
molecular iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable dye and
quinine. The numbers in study 2 increased over the review period so that 1365 volunteers were being treated
with molecular iodine by 1989.

INTERVENTIONS: All patients in study 3 had pre- and post-treatment mammography and measurement of
serum triiodothyronine, thyroxine and thyroid-stimulating hormone levels. MAIN OUTCOME MEASURES:
Subjective evaluation--freedom from pain--and objective evaluation--resolution of fibrosis.

RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical improvement in their breast disease,
but the rate of side effects was high; 40% of patients treated with protein-bound iodide had clinical improvement.
Study 2: 74% of patients in the crossover series had clinical improvement, and objective improvement was noted
in 72% of those who received molecular iodine initially. Study 3: in the treatment group 65% had subjective and
objective improvement; in the control group there was a subjective placebo effect in 33% and an objective
deterioration of 3%.

CONCLUSIONS: The fibrocystic breast reacts differently to sodium iodide, protein-bound iodide and molecular
iodine. Molecular iodine is nonthyrotropic and was the most beneficial.

The Effects of Iodine and Iodide on Iodine Deficient Rat Breast and Thyroid Tissues, Experiment XII:10.
Arnold SJ, Griffin AS, Eskin BA
July 1989.

Conclusions: (1) Iodine deficiency is correlated with mammary tissue atypia, which resembles fibrocystic
disease in humans.  (2) Estrogen enhances the active condition of the breast and any therapies acting upon the
breast tissue in rats.  (3) Iodine reverses the histology of fibrocystic disease in rat breasts.  (4) Iodine is more
therapeutic in the rat breast than iodide.  (5) Iodide has a minimal effect on the rat breast but is effective in the
thyroid.  (6) Potassium iodide improves the iodine deficient thyroid condition, but proves to be an inadequate
therapy for the fibrocystic disease and other breast atypia that occurs.

Fibrocystic Breast Dysplasia:  An Abridged Laboratorical and Clinical Summary
Ghent WR, Eskin BA
Proceedings of World Congress of Surgery, 1989, 33:622.

Conclusion:  Laboratorical and clinical studies suggest that the fibrocystic syndrome is a manifestation of a trace
element deficiency in the form of iodine I2.  Subjective and objective improvement approached 90% when
patients with breast complaints were given this replacement therapy.

Iodoprotein formation by rat mammary glands during pregnancy and early postpartum period.
Shah NM, Eskin BA, Krouse TB, Sparks CE.
Proc Soc Exp Biol Med. 1986 Mar;181(3):443-9.
[abstract only]

Iodide organification by rat mammary glands was studied during the trimesters of pregnancy and early
postpartum period. Organification was followed by measuring trichloroacetic acid (TCA) precipitation of
delipidated tissue homogenates. The radiolabeled material was sensitive to proteolytic cleavage by a bacterial
protease indicating that the 125I was protein-bound. Gel filtration column chromatography in the presence of
sodium dodecyl sulfate (SDS) of delipidated mammary tissue homogenates of pregnant and postpartum rats
reproducibly resolved several iodoproteins from free iodide. The Kav value for each iodoprotein peak was
calculated and was used to estimate each subunit molecular weight which averaged 37,500, 25,100, and 8500.
Another iodoprotein with a very large subunit molecular weight of greater than 300,000 was also detected in
mammary tissue. Incorporation of 125I-iodide into the three smaller iodoproteins increased logarithmically from
the start of the second trimester of pregnancy through the early postpartum period when approximately 20% of
the total 125I uptake by mammary tissue was incorporated into protein. Hyperplasia, acinar development, and
intracytoplasmic vacuolization of mammary tissue correlated with the increased incorporation of 125I-iodide into
these iodoproteins. The characterization and quantitation of specific iodoproteins in mammary tissue may be
important as organification of iodide is believed to be a marker for normal hormone-responsive cells.

Iodine Deficiency Breast Syndrome
Ghent WR, Eskin BA.
Frontiers in Thyroidology, Proceedings of the Ninth International Congress.  1985. Medeiros-Neto G, Gaitan E
(eds).

The etiology of fibrocystic dysplasia has remained obscure. The theories have included a prolonged Luteal
phase, a reversal of the Oestrone/Oestriol ratio, increased median prolactin levels, or any upset in these
complex interrelationships. All of these etiological theories are supported by good research data and should not
be dismissed out of hand.... We would postulate that there is a common denominator underlying all of these
concepts, and this is an iodine deficiency state. In this state, it is further postulated that the secreting cells of the
breast are sensitized to various stimuli to produce the changes noted. This sensitization can progress to overt
malignancy if a carcinogen is added.... The rat model of Eskin strongly supports the iodine deficiency theory. The
clinical improvement rate of 93.4% is impressive and considerably above other forms of treatment.... A further
reinforcement is the 89.5% recidivism rate upon cessation of treatment.

Mammary Gland Hormone Receptors in Iodine Deficiency
Eskin BA, Mitchell MA, Modhera PR
Proc Endocr Soc, 1985; 67:324.  [abstract]

Iodine deficiency (ID) in rats causes specific histological and biochemical mammary gland changes.  
Histologically: atypia, hyperplasia, hypersecretion and fibrosis occur.  Biochemically: evidence of increased
iodine uptakes, decreased iodinated protein in duct and acinar cells, and quantitative differences in the form of
estradiol receptor (4-5S 8-9S) have been reported.  These effects of ID are intensified when endogenous
estrogen is given.  In order to determine whether ID affects hormone receptor binding capacity, virgin female rats
made iodine deficient were given 50 mcg estradiol (E), 16 mcg iodine/day (I) or both E+I.... Mammary gland
estrogen receptor (ER) and progestin receptor (PR) were measured.... ER values are low, while PR shows high
binding capacities.  Previous work has shown that iodination in the breast is dependent on hormonal
stimulation.  This preliminary data indicates that hormonal binding capacity may be dependent on available
iodine.

Age-related changes resembling fibrocystic disease in iodine-blocked rat breasts.
Krouse TB, Eskin BA, Mobini J
Arch Pathol Lab Med. 1979 Nov;103(12):631-4.

It has been reported that dietary restriction and chemical blockade of iodine causes histopathologic changes in
peripubertal female rat breasts. This study extended the age range to include midreproductive life and
perimenopausal rats; there is a wider spectrum of structural alterations that are associated with the older breast,
with sodium perchlorate as the blocking agent. In 16-week-old rats, breasts showed general increased
parenchymal activity and growth, regressing after removal of the block. In 42-week-old rats, breasts showed
noticeable calcospherite deposition, intralobular fibrosis, and cystic changes resembling human fibrocystic
disease. In 52-week-old rats, breasts exhibited atypical lobules cytologically, papillomatosis, sclerosing
adenosis, calcifications, and a lobular transformation of a histologically dysplastic type. It is the older rat that
experiments will more closely parallel the human condition.

Protein Iodination in the Breast and Thyroid of Rats
Eskin BA, Sparks CE, LaMont B, Kolonsky D
Proc Endocr Soc, 1978; 60: 394.  [abstract]

We have measured I-125 iodide uptake and protein iodination in normal and lactating breasts and respective
thyroids of rats in vivo....Rapid uptake and organification of iodide may be an important function of active breast
tissue.

Iodine and Mammary Cancer
Eskin BA
Adv Exp Med Biol. 1977;91:293-304.

From laboratory studies presented, iodine appears to be a requisite for the normalcy of breast tissue in higher
vertebrates. When lacking, the parenchyma in rodents and humans show atypia, dysplasia, and even neoplasia.
Iodine-deficient breast tissues are also more susceptible to carcinogen action and promote lesions earlier and
in greater profusion. Metabolically, iodine-deficient breasts show changes in RNA/DNA ratios, estrogen receptor
proteins, and cytosol iodine levels. Clinically, radionuclide studies have shown that breast atypia and malignancy
have increased radioactive iodine uptakes. Imaging of the breasts in high-risk women has localized breast
tumors. The potential use of breast iodine determination to determine estrogen dependence of breast cancer
has been considered and the role of iodide therapy discussed. In conclusion, iodine appears to be a compulsory
element for the breast tissue growth and development. It presents great potential for its use in research directed
toward the prevention, diagnosis, and treatment of breast cancer.

Human breast uptake of radioactive iodine.
Eskin BA, Parker JA, Bassett JG, George DL
Obstet Gynecol. 1974 Sep;44(3):398-402.

Increased radioiodine uptake parallels the abnormal breast tissue changes produced by iodine deficiency in
rats.  Pilot studies show that I-131 concentration in biopsied human breast tissues with carcinoma or dysplasia
is higher than in histologically normal tissues from the same patient.  In a two-part study employing I-131 and I-
123 as the radionuclide tracers, evidence is presented showing that radioiodine uptakes in human breasts can
be determined in vivo, that normal values by the technic employed were 10% or less, and that abnormal (i.e.,
dysplastic or neoplastic) breast tissue has increased radioiodine uptake.

Mammary gland dysplasia in iodine deficiency. Studies in rats.
Eskin BA, Bartuska DG, Dunn MR, Jacob G, Dratman MB
JAMA. 1967 May 22;200(8):691-5.

Iodine deficiency was found to enhance the response of rat breast tissues to sex-hormone injections; the breast
changes seen in the iodine-deficient rat were clearly distinguishable from those induced by sex hormones in the
hypothyroid and in the euthyroid rat. Estrogen and testosterone administration to iodine-deficient hypothyroid rats
resulted in lesions which mimic human cystic disease of the breast. Thus the present study suggests another
physiologic factor which may act to modify breast-sex steroid interactions.
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