Annotated References:
Investigating the Relationship Between Iodine and the Breast
Breastcancerchoices.org
Innovative Research and Patient Advocacy


PART 3: WHAT IS THE EFFECT OF IODINE ON BREAST CANCER?

  • A 2005 Breast Cancer Patient-Iodine Study Finds Patients Low in Iodine

Editor's Note: Using the screening iodine-loading test, a small preliminary breast cancer-iodine study found that there is a significant decrease in excretion of urinary iodine in women with
breast cancer, implying iodine-deficiency.  Previous studies have shown that there is less iodine
in malignant breast tissue, and this study indicates that iodine plays a role in breast cell
differentiation.

Identification of Breast Cancer by Differences in Urinary Iodine
(Abstract Number: 2150)96th Annual Meeting AACR, April 16-20, 2005, Anaheim/Orange
County, CA By Bernard A. Eskin, Waqas Anjum, Guy E. Abraham, Frederick Stoddard, Ann
Prestrud, Ari D. Brooks, Drexel University College of Medicine, Philadelphia, PA, Optimox
Corporation, Torrance, CA.

Introduction: Iodine is involved metabolically in normal, nursing, and neoplastic breast tissues.  
Our objective was to evaluate differences in urinary iodine levels in women with benign and
malignant breast changes.  Methods:  Ninety-eight women with a median age of 47 years
(range 15-87) presenting with benign or malignant breast diagnoses to the university breast
center participated in this study.  Women with a history of hyper/hypothyroidism were excluded.  
Urine specimens were collected following informed consent.  Urine was quantified by
chromatography/anion exchange resin.  Values are reported as micrograms (mcg) iodine or
milligrams (mg) bromide per liter by ion selective electrode assay.  A t-test was used to
compare means.  Results:  Our final cohort included 20 women with cancer (DCIS=6, invasive
cancer=14), 20 women who were smokers and 42 who were post menopausal.
A significant difference in iodine excretion between women with cancer (105 mcg/l) versus non-
cancer (141 mcg/l, p<0.05) was demonstrated.
Trends seen were: 1) Higher excretion (26%) in postmenopausal versus premonopausal
women (152 mcg/l vs. 121 mcg, p=NS). 2) Smokers had lower (23%) iodine excretion (109
mcg/l vs. 141 mcg/l, p=NS). 3) Lower iodine excretion in women with cancer, regardless of
menopausal status.
In order to control for halide effect, urinary bromide level was determined in a subset of these
women (n=47). Urinary bromide levels trended towards higher excretion by 64% in women
without cancer (18.5 mg/l vs. 11.3 mg/l, p=NS), in premenopausal women by 36% (20.5 mg/l vs.
15.1mg/l, p=NS), and smokers by 35% (22.7 mg/l vs. 16.8 mg/l, p=NS).
Discussion:  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.


  • A 2006 Breast Cancer Patient-Iodine Study
    Finds Patients Low in Iodine, High in theToxins Bromine and Fluoride

Brownstein, D., Iodine.  Why You Need It, Why You Can't Live Without It, 2nd Edition, Medical
Alternatives' Press 2006.

Editor's Note: Dr. David Brownstein, using the iodine-loading test, conducted a very small study
in his practice to determine the iodine, bromine, and fluoride levels in eight breast cancer
patients and ten non-breast cancer patients.  Results:  The iodine levels were low in all of the
patients.  Just as the levels of the toxin, bromide,  trended higher in the breast cancer patients in
the Eskin study cited above, in this study,  the bromide levels similarly were significantly
elevated in  the breast cancer patients as opposed to the non-breast cancer patients.  Also, the
levels of the toxin, fluoride, were higher in the breast cancer patients.  Supplementing with
iodine will rectify the iodine deficiency and importantly help the body detox these toxins.


  • Continuous Administration of Iodine to Rats Results in Strong and Persistent
    Reduction of Incidence of  Breast Tumors

Editor's Note:  In this 2005 study, the continuous treatment of rats with iodine exhibited a potent
protective effect (70%) on breast tumors induced by the carcinogen, MNU.  This effect is exerted
by iodine, but not by iodide or T4.  Any interruption of the iodine treatment resulted in an
increased incidence of tumors.The suppression by iodine treatment is accompanied by the
development of latent tumors that do not progress to overt cancers, suggesting that the
mechanism of action is at the promotional level,  and the protective mechanisms may involve
regulating the oxidative environment.

Mol Cell Endocrinol. 2005 May 31;236(1-2):49-57. Epub 2005 Apr 13.
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.
by Garcia-Solis P, Alfaro Y, Anguiano B, Delgado G, Guzman RC, Nandi S, Diaz-Munoz M,
Vazquez-Martinez O, Aceves C.
Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Km 15 Carretera Qro-
SLP, Juriquilla, Queretaro 76230, Mexico.

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.

  • Iodine, with Added Progesterone, Has a Stronger Effect Than Iodine Alone on Breast
    Tumors in Rats

Editor's Note: Adding iodine to chemically-induced (DMBA) rat breast tumors had a suppressive
effect on the growth of tumors. Adding iodine plus medroxyprogesterone (progesterone) gave
the highest level of response.  The growth-suppressed tumors showed 100% times the iodine
content than the full blown (nonsuppressed) tumors.

J Surg Oncol. 1996 Mar;61(3):209-13. Related Articles, Links  
Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat
by Funahashi H, Imai T, Tanaka Y, Tobinaga J, Wada M, Morita T, Yamada F, Tsukamura K,
Oiwa M, Kikumori T, Narita T, Takagi H.
Department of Surgery II, Nagoya University School of Medicine, Japan.

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.

  • Seaweed's Anti-Cancer Effect on Rats

Editor's Note:  Rats fed 5% Laminaria, a brown seaweed, then given the carcinogen, DMBA, had
a delayed time to the occurrence of tumors and fewer adenocarcinomas.

Cancer Res. 1984 Jul;44(7):2758-61
Dietary seaweed (Laminaria) and mammary carcinogenesis in rats
by Teas J, Harbison ML, Gelman RS.

To test the potential in vivo antitumor effect of dietary seaweed, we induced mammary tumors in
female Sprague-Dawley rats with the carcinogen 7,12-dimethylbenz(a)anthracene. Twenty-one-
day-old rats (n = 108) were divided into two groups. Controls were fed a standard semipurified
diet, and experimental rats received the control diet with 5% Laminaria, a brown seaweed,
replacing 5% alphacel . At 55 days of age, each rat received 5 mg 7,12-dimethylbenz(a)
anthracene intragastrically. Rats were palpated for mammary tumors and weighed weekly for
26 weeks. Complete autopsies were then done on all rats. The seaweed diet did not alter
weight gain or weights of body organs at autopsy. Experimental rats had a significant delay in
the time to tumor (p = 0.007); median time until tumor was 19 weeks in experimental rats and
11 weeks in control animals. Among mammary adenocarcinoma tumor-bearing animals,
experimental rats had fewer adenocarcinomas/individual (p less than 0.05). There was also an
overall 13% reduction in the number of experimental rats with histologically confirmed
adenocarcinomas (76% among the control rats compared to 63% among the experimental
rats). Components of Laminaria which might account for the observed difference in mammary
tumor growth are varied and include the sulfated polysaccharide fucoidan . Rats in the top row
of cages had a significant (p = 0.01) delay in time to tumor compared to rats in the lower four
rows. In each row, the seaweed-fed rats had a longer time to tumor than did the control rats.

  • Iodine-Rich Seaweed Exhibits an Anti-cancer Effec on Rats Fed 1.0% and 5.0%
    Wakame Seaweed

Editor's Note: When rats were fed lesser amounts of seaweed,1.0% and 5.0% of wakame
seaweed, then given the carcinogen, DMBA, there was  similarly a significant suppression of
tumor growth and delay to the time of tumor occurrence.

Jpn J Cancer Res. 1999 Sep;90(9):922-7.
Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)-anthracene-
induced mammary tumors in rats.

by 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.
Department of Surgery II, Nagoya University School of Medicine. hfunahas@tsuru.med.nagoya-
u.ac.jp

We examined the anti-tumor proliferation effects of wakame seaweed on 7,12-dimethylbenz(a)-
anthracene (DMBA)-induced rat mammary tumor. DMBA was administered to 8-week-old
female Sprague-Dawley rats, and rats which developed mammary tumors were assigned
randomly to three groups. Commercial rat feed was used in a control group (group I-A), and two
feed mixtures were prepared, which contained commercial rat feed blended with wakame at
1.0% (group I-B) and 5.0% (group I-C) by weight. The respective feeds were given to each group
for 8 weeks, and changes in mammary tumor size were compared. At the end of the
experiment, mammary tumors and thyroid glands were resected to compare their weights.
Serum total iodine and thyroxin (T4) levels were measured. Immunohistochemical studies for
bromodeoxyuridine (BrdU) labeling, transforming growth factor (TGF)-beta, and apoptosis were
carried out in the resected 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.seaweed-fed rats had a longer time to tumor than did the control rats.


  • Seaweed's Anti-Cancer Effect on Human Breast Cancer Cells Iodine-Rich Mekabu
    Seaweed Exhibits an Anti-cancer Effect In the Lab on Human Breast Cancer Cells

Editor's Note: In the lab, mekabu, which is a part of the wakame seaweed plant, induced cell
death in three kinds of human breast cancer cells.  Mekabu had a more potent effect on the
cancer cells than the chemo drug, 5-fluorouracil, that is used to treat breast cancer.  The
researchers speculated that "seaweed may be applicable for prevention of breast cancer".

Jpn J Cancer Res. 2001 May;92(5):483-7.
Seaweed prevents breast cancer?
by 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.
Department of Surgery II, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550,
Japan.

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.

  • Iodine + Selenium:  Selenium is Needed For Proper Functioning of Iodine

Editor's Note:  Deiodinase enzymes which convert T4 (thyroxine, the prohormone that has four
atoms of iodine ) into T3 (triiodothyronine, the cellularly active hormone that has three atoms of
iodine), and then convert T3 into T2 are selenium-dependent.  In addition to being incorporated
into thyroid hormones, iodine is organified into anti-proliferative iodilipids in the thyroid;  such
compounds may play a role in the proliferative control of other tissues, such as the breast.  
Selenium acts synergistically with iodine.  Thus, selenium may affect hormone homeostasis and
iodine availability.  

Cancer Causes Control. 2000 Feb;11(2):121-7.
Hypothesis: iodine, selenium and the development of breast cancer.
Cann SA, van Netten JP, van Netten C.
Special Development Laboratory, Royal Jubilee Hospital, Victoria, BC, Canada.

BACKGROUND: In this paper we examine some of the evidence linking iodine and selenium to
breast cancer development. Seaweed is a popular dietary component in Japan and a rich
source of both of these essential elements. We hypothesize that this dietary preference may be
associated with the low incidence of benign and malignant breast disease in Japanese
women. In animal and human studies, iodine administration has been shown to cause
regression of both iodine-deficient goiter and benign pathological breast tissue. Iodine, in
addition to its incorporation into thyroid hormones, is organified into anti-proliferative iodolipids
in the thyroid; such compounds may also play a role in the proliferative control of extrathyroidal
tissues. Selenium acts synergistically with iodine. All three mono-deiodinase enzymes are
selenium-dependent and are involved in thyroid hormone regulation. In this way selenium
status may affect both thyroid hormone homeostasis and iodine availability. CONCLUSION:
Although there is suggestive evidence for a preventive role for iodine and selenium in breast
cancer, rigorous retrospective and prospective studies are needed to confirm this hypothesis.

  • Taking Vitamin C with Iodine

Vitamin C:  Using Nutrition to Improve Iodine Transport Defect To Help Iodine Enter Cells
Abraham GE and Brownstein D., Evidence that the Administration of Vitamin C Improves a
Defective Cellular Transport Mechanism for Iodine: A Case Report, The Original Internist 2005.

(There is no abstract available.  To read the entire study, go to: http://www.optimox.
com/pics/Iodine/IOD-11/IOD_11.htm)

Editor's Summary:
Drs. Abraham and Brownstein describe a case of using nutrition - vitamin C and chloride - to
improve the function of a defective iodine cellular transport system to help iodine enter cells. To
help enable iodine to be absorbed by the cells, two iodine transport systems, the sodium/iodide
system (NIS) - one atom of iodine is transported into cells and two atoms of sodium are
transported out of cells,  and the chloridide/iodide (pendrin) system help facilitate the
transportation of iodine into cells.  Rarely, these iodine cellular transport systems can become
blocked or damaged, leaving cells iodine-deficient.  In this case report, on an iodine-loading
test, a woman excreted 90% of the iodine, which usually implies iodine sufficiency, but the high
excretion rate was coupled with a low serum inorganic iodide level, suggesting  a defect in the
iodine retention mechanism.  She also had elevated levels of bromide - a toxic halide - in her
urine and serum.  The elevated bromide may have caused oxidative damage to the iodine
transport system. Since chloride competes with bromide and increases the elimination of
bromide, chloride was administered at 10mg/day for one week.  The result:  A marked increase
in bromide excretion.  Plus, she was given the antioxidant vitamin C at 3gm/day for three
months. At the end of three months of nutrititonal support, she increased her baseline serum
inorganic iodide level, and her retention of  iodine was increased from 10% to 50%.  This case
report presents evidence of nutrition  helping to improve the function of the iodine cellular
transport mechanism.

IODINE AND BREAST CANCER SUMMARY:  Does Iodine Act as an Anti-Estrogen, Like  the
Drugs, Arimidex and Tamoxifen?

From Eskin BA's study,  Iodine and Mammary Cancer, cited in the IODINE and BENIGN BREAST
DISEASE section, iodine is stated to be a requisite element for normal breast tissue.  Iodine
deficient tissues show changes in, among other things, estrogen receptor proteins.  
Supplementing with iodine would make the breast tissue less susceptible to stimulation from
excess iodine, which is produced by the ovaries in an iodine-deficient state and courses
through the blood. Thus, iodine acts as an anti-estrogen.

Arachidonic acid (polyunsaturated fats) and its metabolites, COX and LOX, exert a
dedifferentiative effect on breast tissue.  "PGE2, as a product of cyclooxygenase (COX),
stimulates the gene expression of aromatase in the fatty tissue of the breast, whereby
intramammary estrogen increases". (Torremante P., Mastopathy, Breast Cancer and
Iodolactones, cited in the IODINE'S  MECHANISMS of ANTI-TUMOR ACTION section.) Plus, in
the Hartmann et al. study in the IODINE and BENIGN BREAST DISEASE section, the 41 out of
235 women who had atypia who went on to develop breast cancer, had significantly higher
levels of COX-2 or cyclooxygenase-2, the enzyme produced in the body when there is
inflammation and which is also produced in precancerous tissues.

When arachidonic acid becomes iodinated (bound to iodine), the iodolactones that are formed
inhibit the EGF (epidermal growth factor) receptor, whereby the metabolism of arachidonic acid
induced by EGF and TGFa (powerful growth factors) is inhibited.

Thus, powerful arguments can be made that iodine may be a de facto anti-estrogen and
aromatase inhibitor in the manner of the drugs, Arimidex and Tamoxifen.

  • Calling for Iodine to be Considered as an Adjuvant Therapy for Breast Cancer

Carmen Aceves,  in her review article,  Is Iodine a Gatekeeper of the Integrity of the Mammary
Gland?, cited in the IODINE'S MECHANISMS of ANTI-TUMOR ACTION section, states,  "We
propose that  an I2 (iodine) supplement should be considered as an adjuvant in breast cancer
therapy."