Scrutinizing the evidence for breast
cancer procedures and treatments
References:  What is the background of iodine and breast disease risk?
What are iodines's mechanisms of action?
Breast Cancer Choices reviews the peer reviewed literature

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  • Geographical Areas of Iodine Deficiency Lead to Increased Risk of
    Breast Cancer

    Editor's Note: The author below found that from 1990-1993, the US had 22.3
    deaths per 100,000 women of breast cancer, placing them in 45th place in the
    world, while in Japan, where they have high dietary iodine, there were 6.6
    deaths per 100,000, placing them in 13th place (Cancer Statistics, 1997).
    These findings tally with the study below finding that the low intake of dietary
    iodine, found due to geographical differences, leads to a risk of breast,
    endometrial, and ovarian cancer.

    Lancet. 1976 Apr 24;1(7965):890-1.
    Dietary Iodine and Risk of Breast, Endometrial, and Ovarian Cancer
    by Stadel BV

    Geographic differences in the rates of breast, endometrial, and ovarian cancer
    appear to be inversely correlated with dietary iodine intake.  Endocrinological
    considerations suggest that a low dietary iodine intake may produce a state of
    increased effective gonadotrophin stimulation, which in turn may produce a
    hyperoestrogenic state characterised by relatively high production of oestrone
    and oestradiol and a relatively low oestriol to oestrone plus oestradiol ratio.  
    This altered endocrine state may increase the risk of breast, endometrial, and
    ovarian cancer. Increasing dietary iodine intake may reduce the risk of these

  • Estrogen Receptors More Sensitive to Estrogen When Iodine

    Editor's Note: The author below found iodine-deficient breasts show changes
    in RNA/DNA ratios, estrogen receptor proteins, and cytosol iodine levels.
    Iodine is a necessary element for breast tissue growth and development.  

    Adv Exp Med Biol. 1977,91:293-304
    Iodine and mammary cancer.
    by Eskin BA.

    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.   

  • Iodine Deficiency Increases Ovarian Production of  Estrogen

    Editor's Note: The 2005 study below found that ovarian estrogen production
    increases during an iodine-deficient state, while changes in the estrogen
    receptors in iodine-deficient breasts make them more sensitive to circulating
    estrogens (Eskin above).  A diet low in iodine can lead to a hyperestrogen
    state with high estrone and estradiol and a low estriol to estrone ratio that can
    lead to cancer (Stadel above).

    Domest Anim Endocrinol. 2005 Jul;29(1):97-103. Epub 2005 Apr 7.
    Ovarian iodide uptake and triiodothyronine generation in follicular fluid. The
    enigma of the thyroid ovary interaction.
    by Slebodzinski AB.

    Polish Academy of Sciences, ul. Promienista 166A/34, 60-157 Poznan, Poland.

    Since 1928, the iodine concentration in the ovary has been known to be higher
    than in every other organs except the thyroid. The ovarian iodide uptake varies
    with sexual activities, is enhanced by estrogens and a hypothyroid state and
    blocked by goitrogens. The recent discovery of a sodium iodide symporter
    (NIS) in ovaries has offered a possible mechanism for ovarian iodide uptake
    and other functional similarities to its thyroid counterpart. Nevertheless, the
    physiological significance of ovarian iodine uptake and accumulation remains
    unknown. The presence of thyroid hormones (TH) in follicular fluid (FF) has
    been established recently. Our preliminary studies on TH in FF (1996-1998) in
    rabbits, pigs, horses showed that the concentration of T4 is generally lower
    than that in serum and that for T3 is within the normal range or higher. A
    positive correlation exists between the T4 levels in FF and serum but not
    between the corresponding T3 levels. These studies revealed, for the first
    time, the presence of the ovarian 5'-monodeiodinase system in FF capable of
    generating T3 (ovary-born T3) by outer ring deiodination of T4. In mares,
    seasonal polyestrus, ovarian 5'-monodeiodinase (MD) activity and FF T3 levels
    have been found to be higher during the ovulatory period than in the
    anovulatory one. The exact physiological significance of this system
    generating T3 and coexisting with isoforms of TH receptors in granulosa cells
    has not been elucidated. A direct role of T3 for the early follicular development,
    differentiation and for the steroidogenic capability of granulosa cells, although
    strongly suggested by data obtained from in vitro studies, has to be elucidated.

  • Effect of Blocking Iodine in Rats Causes Human-Like Fibrocystic

    Editor's Note: The authors below found that blocking dietary iodine and
    imposing a chemical blockade of iodine in female rats, from the
    midreproductive to perimenopausal years, progressively caused human-like
    fibrocystic disease in the rats. The older 52-week-old rats exhibited atypical
    lobules, papillomas, sclerosing adenosis, calcifications, and lobular dysplasia.

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

    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.

  • Iodine, as Opposed to Iodide,  Effective in Diminishing Ductal
    Hyperplasia and Perilobular Fibrosis Secondary to Iodine Deficiency

    Editor's Note: The authors below observed that for iodine-deficient rats that
    manifest atypical breast and thyroid tissues, supplementing with iodine helped
    with the breast and iodide helped with the thyroid.

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

    Department of Obstetrics and Gynecology, Medical College of Pennsylvania,
    Philadelphia 19129, USA.

    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.

  • Benefits of Supplementing  Iodine in Women with Fibrocystic
    Disease: Breast Reduction + Reduced Symptoms

    Editor's Note: As cited above, for iodine-deficient rats, iodine was more
    beneficial than iodide for the mammary gland. Similarly, for  humans with
    fibrocystics breasts, the patients incurred more benefits from supplementing
    with iodine rather than iodide.  The benefits included a reduction in breast size
    and remission of disease symptoms.

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

    Department of Surgery, Queen's University, Hotel Dieu Hospital, Kingston, Ont.

    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 nonthytropic
    and was the most beneficial.

  • Breast Pain Associated with Fibrocystic Disease: Iodine Helped
    Relieve Symptoms in Dose-Dependent Manner

    Editor's Note: The author below found patients with breast pain associated
    with fibrocystic disease experienced iodine-dependent symptom relief after
    taking iodine. Of patients taking 1.5 mg., 3.0 mg., or 6.0 mg. a day of iodine for
    six months for breast pain associated with fibrocystic disease, more than 50%
    of patients taking 6.0 mg. for six months reported less pain. After five months,
    physician assessment of reduction in pain, tenderness and nodularity was
    seen in the women taking 3.0 mg. and 6.0 mg. of iodine a day - but not in the
    women taking just 1.5 mg. a day.    

    The Breast Journal, Volume 10, Number 4, 2004 328-336
    The Effect of Supraphysiologic Levels of iodine on Patients with Cyclic
    by Jack H. Kessler, Ph.D.

    A randomized, double-blind, placebo-controlled, multicenter clinical trial was
    conducted with 111 otherwise healthy euthyroid women wiht a history of breast
    pain.  Patients had to document moderate or severe breast pain by recording a
    score> 5 on a visual analog scale (VAS) of pain for > 6 days per cycle and had
    to present with fibrosis involving at least 25% of both breast surfaces.  
    Subjects could not be effectively treated wiht more conservative measures
    such as local heat or nonprescription analgesics.  There was not a stastically
    significant difference in the dropout rate for patients on placebo (11.8%), 1.5
    mg/day (31.3%), 3.0 mg/day (18.4%), or 6.0 mg/day (25%) of molecular
    idodine for 6 months.  Physicians assessed breast pain, tenderness, and
    nodularity each cycle.  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.

  • Breast Pain Associated with Fibrocystic Disease:  Seaweed Helped
    94% of Women Reduce Symptoms

    Editor's Note: The authors below found 94% of patients taking tablets of brown
    sea alga containing iodine, chlorophyll and Omega-3 fats for three months
    experienced pain relief and breast cyst regression.

    Vopr Onkol. 2005;51(2):236-41.
    Investigation of the drug "Mamoclam" for the treatment of patients with
    fibroadenomatosis of the breast
    by Bezpalov VG, Barash NIu, Ivanova OA, Semenov II, Aleksandrov VA,
    Semiglazov VF.

    The clinical trial of a new drug "mamoclam" was carried out in patients with
    benign breast disease. The drug contains omega-3 polyunsaturated fatty
    acids, iodine and chlorophyll derivatives and is produced from the brown sea
    alga laminaria. The study involved 33 patients (mean age 42.5 +/- 1.1 yrs). Two
    tablets were administered thrice a day for three months. Examination included
    clinical evaluation of symptoms of mastopathy and dysalgomenorrhea, breast
    sonography and mammography. Therapeutic response presented as reduced
    mastalgia, premenopausal syndrome, dysmenorrhea and algomenorrhea,
    breast cyst regression as well as attenuated pain associated with benign
    breast disease and palpation. Positive response was reported in 94%. The
    drug should be recommended for benign breast disease treatment.

  • Benign Breast Disease Increases Risk of Developing Breast Cancer

    Editor's Note: In the 2005 Mayo Clinic study below,  benign breast disease ,
    most specifically, the category of  the benign breast lesion, was found to be an
    important factor in the subsequent development of breast cancer. Benign
    breast lesions, biopsied in over 9,000 women,  were classified as either
    nonproliferative,  proliferative without atypia, and atypical hyperplasia, and
    these biopsied women were followed for a median of 15 years to see if they
    developed breast cancer. All of the women had an increased risk of breast
    cancer that persisted for at least 25 years after the biopsy.  "One form of benign
    breast disease, atypical hyperplasia, or atypia, is characterized by abnormal
    cell growth and can be precancerous.  Women with this condition have a four
    times greater risk of developing breast breast cancer."  Of the 235 women with
    atypia (out of the over 9,000 biopsies studied),  41 went on to develop breast
    cancer in 15-20 years. (Abstract No. 2353, AACR presentation, April 2006.)

    N Engl J Med. 2005 Jul 21;353(3):229-37.
    Benign breast disease and the risk of breast cancer
    by 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. Division of Medical
    Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

    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


  • Iodine Treatment Found to Have an Effect on the Expression of
    Breast Cancer Genes

    Editor's Note: Based upon studies finding that iodine deficiency increases breast
    cancer and supplementing with iodine reverses the dysplastic changes, the objective
    of the 2006 microarray genes' analysis of iodine on breast cancer cells was to
    determine the specific molecular pathways through which iodine exerts its protection
    of  breast tissue.  Of 19,000 genes tested,  1600 appeared to have some significance.
    All genes that were up- and down-regulated were examined for common pathways,
    but none were found.  However, 65% were involved in cellular components and 58%
    in physiologic processes.  This study supports the hypothesis that iodine does effect
    gene expression in breast cancer cells, and the lack of a common pathway may
    involve other uncharacterized genes.

    Microarray Characterization of Iodine Metabolic Pathways in Breast Cancer
    (Page 379)
    by Eskin, Bernard; Stoddard H, Frederick; Brooks, Ari
    Drexel University College of Medicine, Philadelphia, United States

    Background: The metabolic iodine pathway critical to the thyroid is simulated in a
    wide range of non-thyroidal tissues, including the female breast.  Iodine deficiency
    has been shown to increase the incidence of breast carcinoma and iodine
    replacement reverses the dysplastic changes that occur;  iodine protects breast
    tissue from malignant change.  Since the specific molecular pathways through which
    iodine affects breast tissue is yet unknown, we are using RNA profiling experiments
    to examine the effect of iodine treatment on gene expression in breast cancer cells
    Experiment:  Human breast cancer MCF-7 cells were grown in medium containing
    either 0 (control), 0.1, or 1.0 uM of iodine for 24 hours.  RNA was isolated and
    subjected to microarray analysis using arrays containing approximately 19,000
    genes.  Comparisons were made between the control and the two test conditions
    (either 0.1 or 1uM iodine).  Ratio of the Medians (Rm) was used to compare signal
    intensities between groups.
    Results:  Of the 19,000 genes, 1,600 demonstrated significant signal above
    background.  Rm for the 1.0 uM condition ranged from 3.675 to 0.248 while the 0.1 uM
    condition ranged from 1.774 to 0.46.  Out of these 1,600 genes, approximately
    0.375% was up regulated (Rm > 1.7) and 0.375% were down regulated (Rm < 0.5).  
    All genes that were up-or down-regulated from the 1.0 uM array were analyzed for
    common pathways and cellular processes.  No common pathways were identified;  
    however, 65% of the genes were found to be involved in cellular components and
    58% involved in physiologic processes.  Among the down-regulated genes in the 1.0
    uM condtion there was consistence between the 1.0 and 0.1 uM Rm.  This
    consistency was not apparent in the up-regulated genes.

    Conclusion:  Our data supports the hypothesis that iodine effects gene expression in
    the MCF-7 cell line.  Understanding alteration in genes expression in response to
    iodine may provide insight into the breast iodine pathway responsible for iodine's
    protective effects on the female breast. Although this study does not indicate a known
    common pathway, the breast iodine pathway may involve yet uncharacterized genes.

  • Iodine's Three Ways of Action

    Editor's Note: The authors below found three principal iodine actions: 1.  As an
    antioxidant by exerting a competition with free radicals for membrane lipids, protein,
    and DNA to help stabilize the cells. 2.  As inducers of antiproliferative and apoptotic
    mechanisms through the formation of iodolactones. 3.  As a part of thyroid hormones.

    J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):189-96. Related Articles, Links  
    Is iodine a gatekeeper of the integrity of the mammary gland?
    by Aceves C, Anguiano B, Delgado G.
    Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Juriquilla

    This paper reviews evidence showing iodine as an antioxidant and antiproliferative
    agent contributing to the integrity of normal mammary gland. Seaweed is an important
    dietary component in Asian communities and a rich source of iodine in several
    chemical forms. The high consumption of this element (25 times more than in
    Occident) has been associated with the low incidence of benign and cancer breast
    disease in Japanese women. In animal and human studies, molecular iodine (I(2))
    supplementation exerts a suppressive effect on the development and size of both
    benign and cancer neoplasias. This effect is accompanied by a significant reduction
    in cellular lipoperoxidation. Iodine, in addition to its incorporation into thyroid
    hormones, is bound into antiproliferative iodolipids in the thyroid called iodolactones,
    which may also play a role in the proliferative control of mammary gland. We propose
    that an I(2) supplement should be considered as an adjuvant in breast cancer therapy.

  • Iodine as an Antioxidant

    May 2006 Lab Study on Breast Cancer Cells Shows
    Iodine Exhibits Antioxidant Activity Leading to Apoptosis

    Editor's Note: In the Garcia-Solis study, cited in the Iodine and Breast Cancer section,
    iodine treatment was shown to reduce the incidence of  chemically-induced tumors in
    rats.  Also,  the study found that the progress of breast cancer and its effect may be
    related to the decrease in the oxidative cell environment.  Specifically, there were
    lower levels of lipidperoxidation.  Iodine may act as an antioxidant by competing with
    free radicals for membrane lipids, proteins, and DNA to help stabilize the cells.

    In the lab study below, iodine treatment induced changes in the bcl-2 family of genes,
    leading to the activation and translocation of apoptosis-promoting Bax to the
    mitochondria (where energy is created in the cells).  The subsequent release of
    apoptosis-inducing factor from the mitochondria to the nucleus resulted in the
    destruction of the nucleus, which is cell death.  This study found that iodine exhibits
    strong antioxidant acitivity and thiol depletion seems to play an important role in
    iodine-induced apoptosis.

    J Biol Chem. 2006 May 5
    Molecular iodine induces caspase-independent apoptosis in human breast
    carcinoma cells involving mitochondria-mediated pathway
    by Shrivastava A, Tiwari M, Sinha RA, Kumar A, Balapure AK, Bajpai VK, Sharma R,
    Mitra K, Tandon A, Godbole MM.
    Sanjay Gandhi Postgraduate Institue of Medical Sciences, Lucknow, Uttar Pradesh

    Molecular iodine (I(2)) is known to inhibit the induction and promotion of N-methyl-n-
    nitrosourea-induced mammary carcinogenesis, regresses 7, 12-Dimethylbenz (a)-
    anthracene-induced breast tumors in rat and has also shown beneficial effect in the
    fibrocystic human breast disease. Cytotoxicity of iodine on cultured human breast
    cancer cell lines viz. MCF-7, MDA-MB-231, MDA-MB-453, ZR-75-1 and T-47D is
    reported in this communication. Iodine induces apoptosis in all the cell lines tested,
    except MDA-MB-231 shown by sub-G1 peak analysis using flow cytometry. Iodine
    inhibited proliferation of normal human peripheral blood mononuclear cells, however
    did not induce apoptosis in these cells. Iodine-induced apoptotic mechanism was
    studied in MCF-7 cells. DNA fragmentation analysis confirmed internucleosomal DNA
    degradation. Terminal deoxynucleotidyl transferase-dUTP nick end labeling
    established that iodine induces apoptosis in time and dose- dependent manner in
    MCF-7 cells. Iodine-induced apoptosis is independent of caspases. Iodine
    dissipates mitochondrial membrane potential, exhibits an antioxidant activity and
    causes depletion in total cellular thiol content. Western blot results showed decrease
    in Bcl-2 and upregulation of Bax. Immunofluorescence studies confirmed activation
    and mitochondrial membrane localization of Bax. Ectopic Bcl-2 overexpression did not
    rescue iodine-induced cell death. Iodine treatment induces translocation of Apoptosis
    inducing factor from mitochondria to the nucleus. Treatment of N-acetyl-L-cysteine
    prior to iodine exposure restored basal thiol content, ROS levels and completely
    inhibited nuclear translocation of Apoptosis inducing factor and subsequently cell
    death, indicating that thiol depletion may play an important role in iodine-induced cell
    death. These results demonstrate that iodine treatment activates a caspase-
    independent and mitochondria-mediated apoptotic pathway.

  • Formation of Iodolactones To Suppress Hyperplasia and Tumor Growth

    Editor's Note:  Cann et al., in the article below, write about antiproliferative
    iodolactones. "Antiproliferative iodolactones. This would explain the underlying
    mechanism for iodine-induced suppression of mammary hyperplasia and tumor
    growth."  Cell membranes are composed of lipids (fats).  Iodine can be incorporated
    into these lipids, forming iodolipids. Iodolipids help to stabilize the lipids, help to
    normalize the cell cycle, and inhibit cellular proliferation.  From the Shrivastrava study
    above, "Iodocompounds seem to act as mediators of iodine function as an
    antioxidant."  Iodocompounds inhibit signal transduction pathways induced by growth
    factors, such as epidermal growth factor  Perhaps iodine's antioxdant, antiproliferative,
    apoptosis mechanisms are secondary to the formation of iodocompounds, such as

    The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 821
    Copyright © 1999 by The Endocrine Society
    Iodide Accumulation in Extrathyroidal Tissues
    by Stephen A. Cann, Johannes P. van Netten and David W. Glover
    Royal Jubilee Hospital University of Victoria Victoria, British Columbia, Canada V8R
    1J8 Christiaan van Netten University of British Columbia Vancouver, British Columbia,
    Canada V6T 1Z3

    We read with interest the paper by Spitzweg et al. (1) on human sodium iodide
    symporter (hNIS) gene expression in nonthyroidal tissues. The authors state that
    extrathyroidal tissues are not able to organify accumulated iodide; however, there are
    exceptions to this rule. In addition to thyroperoxidase, other peroxidases found in
    nonthyroidal tissues such as lacto-, myelo-, and eosinophil peroxidase have been
    shown to efficiently organify iodide (2). In the mammary gland, iodide is bound to
    tyrosyl residues of caseins and other milk proteins, and this organification has been
    shown to correlate with peroxidase activity (3, 4). In addition, there is evidence that
    iodoprotein formation may occur in inactive mammary tissue as well (5). Thus, it is
    not unreasonable to assume that more extensive iodide organification may occur in
    other tissues.

    Although iodide uptake in nonthyroidal tissues does not appear to be influenced by
    TSH, a number of other hormones are known to augment its accumulation. In mice,
    prolactin has been shown to enhance mammary iodide uptake during pregnancy (6).
    In nonpregnant rats, estradiol has been shown to significantly enhance mammary
    iodide accumulation (7). Conversely, estradiol has been shown to inhibit, while
    progesterone enhances, iodide uptake in the rat uterus and oviduct (8). Thus, a
    dynamic iodide balance may be maintained in these nonthyroidal tissues depending
    on the hormonal milieu and dietary iodine levels.

    What role might iodide play in these nonthyroidal tissues? In addition to its
    incorporation into thyroid hormones, iodide is also bound, via thyroperoxidase, to
    various lipid molecules (9). These iodolipids have been shown to influence a wide
    range of metabolic functions in the thyroid, including inhibition of cellular proliferation
    (iodolactones) and reduction of H2O2 generation (iodoaldehydes) (9). Interestingly, -
    iodohexadecanal, a naturally occurring iodoaldehyde, has been shown to inhibit
    adenylyl cyclase in kidney cortex and liver membranes, in a fashion similar to its
    activity on thyroid cells (10). Such extrathyroidal activity may also occur with the
    antiproliferative iodolactones. This would explain the underlying mechanism for
    iodine-induced suppression of mammary hyperplasia (7) and tumor growth (11) that
    has been observed in animal models. Furthermore, in tissues that secrete inorganic
    iodide (i.e. stomach, salivary glands, cervix) (12), its accumulation through the hNIS
    symporter and subsequent oxidation to hypoiodite may be an important aspect of
    mucosal tissue defense (13). A wider physiological role for iodide needs to be
    explored; further research into its accumulation, oxidation and organification, and
    functional activity in nonthyroidal tissues should aid in elucidating these less well
    recognized functions.

    From the conclusion of the 2004 Torremante Study:

    "A source of nutrition which emphasizes seafood and, thereby, provides a source of
    polyunsaturated fatty acids and iodine is a dietary basis for iodolactone formation.  
    This could be the reason for the low incidence of breast cancer in Japan."

    Dtsch Med Wochenschr. 2004 Mar 19;129(12):641-5.

    Mastopathy, breast cancer and iodolactone
    Torremante P.

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