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Iodine Research

Resource Network of The Iodine Movement


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                        Iodine and the Body

Breast pg. 1 (continuation)
________________________________________________________________________________________
Aceves

Uptake and gene expression with antitumoral doses of iodine in thyroid and mammary gland: evidence that chronic
administration has no harmful effects.
Anguiano B, Garcia-Solis P, Delgado G, Velasco CA.
Thyroid. 2007 Sep;17(9):851-9.

Several studies have demonstrated that moderately high concentrations of molecular iodine (I(2)) diminish the
symptoms of mammary fibrosis in women, reduce the occurrence of mammary cancer induced chemically in rats
(50-70%), and have a clear antiproliferative and apoptotic effect in the human tumoral mammary cell line MCF-7.
Nevertheless, the importance of these effects has been underestimated, in part because of the notion that exposure
to excess iodine represents a potential risk to thyroid physiology. In the present work we demonstrate that uptake
and metabolism of iodine differ in an organ-specific manner and also depend on the chemical form of the iodine
ingested (potassium iodide vs. I(2)). Further, we show that a moderately high I(2) supplement (0.05%) causes some
of the characteristics of the "acute Wolff-Chaikoff effect"; namely, it lowers expression of the sodium/iodide symporter,
pendrin, thyroperoxidase (TPO), and deiodinase type 1 in thyroid gland without diminishing circulating levels of
thyroid hormone. Finally, we confirm that I(2) metabolism is independent of TPO, and we demonstrate that, at the
doses used here, which are potentially useful to treat mammary tumors, chronic I(2) supplement is not accompanied
by any harmful secondary effects on the thyroid or general physiology. Thus, we suggest that I(2) could be
considered for use in clinical trials of breast cancer therapies.


Uptake and antiproliferative effect of molecular iodine in the MCF-7 breast cancer cell line.
Arroyo-Helguera O, Anguiano B, Delgado G, Aceves C.
Endocr Relat Cancer. 2006 Dec;13(4):1147-58.

This study analyzes the uptake and antiproliferative effect of two different chemical forms of iodine, iodide (I(-)) and
molecular iodine (I(2)), in MCF-7 cells, which are inducible for the Na(+)/I(-) symporter (NIS) and positive for pendrin
(PDS). The mouse fibroblast cell line NIH3T3 was used as control. Our results show that in MCF-7 cells, I(-) uptake
is sustained and dependent on NIS, whereas I(2) uptake is transient with a maximal peak at 10 min and a final
retention of 10% of total uptake. In contrast, no I(-) was taken up by NIH3T3 cells, and although I(2) was captured with
the same time pattern as in MCF-7 cells, its uptake was significantly lower, and it was not retained within the cell.
The uptake of I(2) is independent of NIS, PDS, Na(+), and energy, but it is saturable and dependent on protein
synthesis, suggesting a facilitated diffusion system. Radioiodine was incorporated into protein and lipid fractions
only with I(2) treatment. The administration of non-radiolabeled I(2) and 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid
(6-iodolactone, an iodinated arachidonic acid), but not KI, significantly inhibited proliferation of MCF-7 cells.
Proliferation of NIH3T3 cells was not inhibited by 20 muM I(2). In conclusion, these results demonstrate that I(2)
uptake does not depend on NIS or PDS; they suggest that in mammary cancer cells, I(2) is taken up by a facilitated
diffusion system and then covalently bound to lipids or proteins that, in turn, inhibit proliferation.


Is Iodine a Gatekeeper for the Mammary Gland?
Carmen Aceves, Brenda Anguiano, Guadalupe Delgado.
J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):189-96.

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....In animal and human studies, molecular iodine (I2) 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. An I2 supplement should be considered as an adjuvant in breast cancer therapy.


Deiodinase type 1 activity is expressed in the prostate of pubescent rats and is modulated by thyroid hormones,
prolactin and sex hormones.
Anguiano B, Lopez A, Delgado G, Romero C, Aceves C.
J Endocrinol. 2006 Aug;190(2):363-71.
Abstract only

The aim of this study was to characterize the type of 5'-deiodinase activity in the prostate of pubescent rats (7-8
weeks), to establish its distribution in the lobes (ventral, dorsolateral, and anterior), and to analyze its modulation by
prolactin (PRL), testosterone, dihydrotestosterone (DHT), and 17beta-estradiol (E(2)). Our results showed that the
enzymatic activity was highly susceptible to inhibition by 6-n-propyl-2-thiouracil and gold thioglucose, its preferential
substrate was reverse tri-iodothyronine (rT(3)), it exhibited a low dithiothreitol requirement (5 mM), and the apparent K
(m) and V(max) values for substrate (rT(3)) were approximately 0.25 microM and 9.0 pmol liberated/mg protein per
hour, respectively. All these characteristics indicate the preferential expression of type 1 deiodinase (D1), which was
corroborated by demonstrating the presence of D1 mRNA in prostate. D1 activity was detected in all lobes and was
most abundant in the dorsolateral. Although we detected type 2 deiodinase (D2) mRNA expression, the D2 activity
was almost undetectable. D1 activity was enhanced in animals with hyperthyroidism and hyperprolactinemia, in
intact animals treated with finasteride (inhibitor of local DHT production), and in castrated animals with E(2)
replacement. In contrast, activity diminished in castrated animals with testosterone replacement. Our results
suggest that thyroid hormones, PRL, and E(2) exert a positive modulation on D1 activity, while testosterone and DHT
exhibit an inhibitory effect. D1 activity may be associated with prostate maturation and/or function"


Regulatory role of the 3' untranslated region (3'UTR) of rat 5' deiodinase (D1). effects on messenger RNA translation
and stability.
Arroyo-Helguera O, Mejia-Viggiano C, Varela-Echavarria A, Cajero-Juarez M, Aceves C.
Endocrine. 2005 Aug;27(3):219-25.
[abstract only]

The previous findings that both a long and a short type 1 deiodinase (D1) mRNA are present in different tissues and
that the D1 gene contains two potential polyA signals suggest that the two mRNAs result from differential polyA
signal usage. In this study, we examined the properties of the two D1 mRNAs generated in HEK 293 cells by the
alternative use of each of the poly A signals in order to ascertain the potential regulatory role of the 3'UTR of this
gene. Our results showed that the long mRNA is less stable, but that it is translated more efficiently than the short
mRNA. The net result of these differences is a higher D1 activity with the long message. These data suggest that the
D1 3'UTR may play an important role in regulating the stability and translational efficiency of the D1 mRNA, both of
which could be physiologically relevant when the demand for D1 activity is high.


Has the mammary gland a protective mechanism against overexposure to triiodothyronine during the peripartum
period? The prolactin pulse down-regulates mammary type I deiodinase responsiveness to norepinephrine.
Anguiano B, Rojas-Huidobro R, Delgado G, Aceves C.
J Endocrinol. 2004 Nov;183(2):267-77.

Peripartum is a crucial period for mammary gland final differentiation and the onset of lactation. Although the 'trigger'
for lactogenesis depends on several hormones, a key factor is the peripartum prolactin (PRL) pulse whose deletion
results in a failure to initiate milk production. Other hormones having a critical role during this period but exerting a
contrary effect are the thyronines. A transitory hypothyroidism occurs at peripartum in serum and several other
extrathyroidal tissues, whereas the induction of hyperthyroidism during late pregnancy is associated with the
absence of lactation after delivery. We analyzed the mammary gland during pregnancy and lactation for: (a) the type
and amount of thyroid receptors (TRs), (b) the local triiodothyronine (T3) generation catalyzed by type I deiodinase
(Dio1), (c) the Dio1 response to norepinephrine (NE) and (d) the effect on Dio1 and TRs of blocking the PRL pulse at
peripartum. Our data showed that during pregnancy the mammary gland contains Dio1 in low amounts associated
with the highest expression of TRalpha1; whereas during lactation the gland shows high levels of both Dio1 and
TRalpha1. However, at peripartum, both TRs and Dio1 decrease, and Dio1 becomes refractory to NE. This
refractoriness disappears when the PRL pulse is blocked by the dopamine agonist bromocriptine. This blockade is
also accompanied by a significant decrease in cyclin D1 expression. Our data suggested that the peripartum PRL
pulse is part of a protective mechanism against precocious differentiation and/or premature involution of the alveolar
epithelium due to T3 overexposure.


Periodontal 5'-deiodination on forced-induced root resorption--the protective effect of thyroid hormone administration.
Vazquez-Landaverde LA, Rojas-Huidobro R, Alonso Gallegos-Corona M, Aceves C.
Eur J Orthod. 2002 Aug;24(4):363-9.

The present investigation was designed to study the protective effect given by thyroid hormone (TH) on root
resorption: (1) whether intra-peritoneal versus oral TH administration had the same efficiency; and (2) whether this
effect involved local or systemic mechanisms. For this purpose, circulating T3 levels, systemic alkaline phosphatase
(APase) activity, and 5'deiodinase (5'D) activity were evaluated in the periodontal area of 80 Sprague-Dawley rats, 8
weeks of age, in which orthodontic appliances had been inserted. The results showed that TH-treated animals (intra-
peritoneal or oral) had significantly less force-induced root resorptive lesions compared with a control group, without
apparent changes in T3 or APase levels, and that periodontal remodelling was accompanied by a significant
increase in local T3 generation as a result of T4 deiodination. This 5'D activity was higher in those animals that
received exogenous TH. These results suggest that this protective TH mechanism may be achieved at a local level
and that administration of low doses of TH may play a protective role on the root surface either during orthodontic
treatment or in those patients that present spontaneous root resorptive lesions.

______________________________________________________________________________________________________
Arturi, Filetti

Regulation of iodide uptake and sodium/iodide symporter expression in the MCF-7 human breast cancer cell line.
Arturi F, Ferretti E, Presta I, Mattei T, Scipioni A, Scarpelli D, Bruno R, Lacroix L, Tosi E, Gulino A, Russo D, Filetti S.
J Clin Endocrinol Metab. 2005 Apr;90(4):2321-6. Epub 2004 Dec 28.

Sodium/iodide symporter (NIS) expression has recently been described in human breast cancer, with emphasis on
its potential exploitation for the treatment of these tumors with radioiodine. In this study, we analyzed the regulation of
NIS expression and function in the MCF-7 human breast cancer cell line. Cell exposure to insulin, IGF-I, IGF-II, or
prolactin induced significant increases in 125I uptake and the expression of both NIS mRNA and NIS protein. The
latter increases were evident after 6 and 12 h of hormonal stimulation, respectively. In immunocytochemistry studies,
NIS was detected mainly in the plasma membrane of MCF-7 cells. A low but significant increase in iodide uptake
was produced by treatment with activators of the adenylyl cyclase (cAMP) or protein kinase C pathways.

Our study demonstrates that: 1) MCF-7 breast cancer cells are capable of active iodide transport that can be
stimulated by insulin, IGF-I, IGF-II, or prolactin; 2) both NIS transcript and protein are expressed in these cells, and
this expression is also hormonally stimulated; and 3) MCF-7 iodide transport and NIS expression may be influenced
by the activation of cAMP or protein kinase C-dependent signaling. These findings increase our understanding of the
molecular mechanisms that regulate NIS expression in breast cancer cells, information that is fundamental for future
research aimed at the development of targeted radioiodide treatment for this type of cancer.
______________________________________________________________________________________________________
Bezpalov

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

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.

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Brown-Grant

Iodinated compounds in milk after radio-iodide administration.
Brown-Grant K, Galton VA
Biochim Biophys Acta. 1958 Feb;27(2):422-3.
[citation only]


The iodide concentrating mechanism of the mammary gland.
Brown-Grant K
J Physiol. 1957 Mar 11;135(3):644-54.

1. The milk/plasma ratio for 131I has been studied for periods up to 6 hr after injection in anaesthetized rabbits and
values between 6.7 and 37.4 were found. Methylthiouracil had no effect on the establishment of a high M/P ratio.

2. The M/P ratio was depressed by various anions, the order of potency being: ClO4- > SCN- >/= I- > IO3 > NO3 >
BrO3-. Bromide and chloride had no effect.

3. A concentration gradient for 131I between milk and plasma was also found in guinea-pigs, rats and mice and was
shown to be reduced by thiocyanate.

4. No evidence was obtained for the concentration of thiocyanate in the milk during inhibition of iodide concentration
by this anion.

5. A small proportion (up to 5%) of the radio-iodine found in rabbit's milk appears to be in organic combination. This
fraction is not seen after methylthiouracil administration.

6. The iodide metabolism of the mammary gland is discussed and compared with that of the thyroid and other extra-
thyroidal iodide concentrating tissues.
_____________________________________________________________________________________________________
Cann

Hypothesis: Iodine, selenium and the development of breast cancer.
Cann SA, van Netten JP, van Netten C.
Cancer Causes Control. 2000 Feb;11(2):121-7. Review.

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 organized 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.

In recent years a second pathway for iodine organification has been described, and involves iodine incorporation into
lipid molecules. These iodolipids have been isolated from thyroid tissue and have been shown to be key regulators
of thyroid cell proliferation and metabolism [53]. Iodide peroxidases (i.e., thyro/lactoperoxidase) catalyze the
iodination of lipids [54]. One such com-pound derived from arachidonic acid, 6-iodo-5-hy-droxy-eicosatrienoic acid (d-
iodolactone), was found to be a potent inhibitor of human thyroid follicular cell proliferation in vitro [55] and to induce
goiter regression in rats in vivo [56]. These or similar compounds may also play a role in the proliferative control of
breast tissue.


Iodide accumulation in extrathyroidal tissues.
Cann SA, van Netten JP, Glover DW, van Netten C.
J Clin Endocrinol Metab. 1999 Feb;84(2):821-2.

We read with interest the paper by Spitzweg et al. 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. 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. In addition, there is evidence that iodoprotein formation may occur in
inactive mammary tissue as well."

"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. In nonpregnant rats, estradiol has been shown to significantly enhance mammary iodide
accumulation. Conversely, estradiol has been shown to inhibit, while progesterone enhances, iodide uptake in the
rat uterus and oviduct. Thus, a dynamic iodide balance may be maintained in these nonthyroidal tissues depending
on the hormonal milieu and dietary iodine levels.

______________________________________________________________________________________________________
Carrasco

Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in
breast cancer cells.
Dohan O, De la Vieja A, Carrasco N.
Mol Endocrinol. 2006 May;20(5):1121-37. Epub 2006 Jan 26.

The sodium/iodide symporter (NIS) mediates a remarkably effective targeted radioiodide therapy in thyroid cancer;
this approach is an emerging candidate for treating other cancers that express NIS, whether endogenously or by
exogenous gene transfer. Thus far, the only extrathyroidal malignancy known to express functional NIS endogenously
is breast cancer. Therapeutic efficacy in thyroid cancer requires that radioiodide uptake be maximized in tumor cells
by manipulating well-known regulatory factors of NIS expression in thyroid cells, such as TSH, which stimulates NIS
expression via cAMP. Similarly, therapeutic efficacy in breast cancer will likely depend on manipulating NIS regulation
in mammary cells, which differs from that in the thyroid. Human breast adenocarcinoma MCF-7 cells modestly
express endogenous NIS when treated with all-trans-retinoic acid (tRa). We report here that hydrocortisone and ATP
each markedly stimulates tRa-induced NIS protein expression and plasma membrane targeting in MCF-7 cells,
leading to at least a 100% increase in iodide uptake. Surprisingly, the adenyl cyclase activator forskolin, which
promotes NIS expression in thyroid cells, markedly decreases tRa-induced NIS protein expression in MCF-7 cells.
Isobutylmethylxanthine increases tRa-induced NIS expression in MCF-7 cells, probably through a purinergic
signaling system independent of isobutylmethylxanthine's action as a phosphodiesterase inhibitor. We also
observed that neither iodide, which at high concentrations down-regulates NIS in the thyroid, nor cAMP has a
significant effect on NIS expression in MCF-7 cells. Our findings may open new strategies for breast-selective
pharmacological modulation of functional NIS expression, thus improving the feasibility of using radioiodide to
effectively treat breast cancer.


The Na+/I- symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in
the thyroid.
Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, Carrasco N.
Clin Cancer Res. 2004 Jul 1;10(13):4294-302.

PURPOSE: The Na(+)/I(-) symporter (NIS) is a key plasma membrane protein that mediates active iodide (I(-))
transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for
the longstanding success of radioactive iodide ((131)I) ablation of metastases after thyroidectomy. Breast cancer is
the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer
metastases (BCM) was unproven.

EXPERIMENTAL DESIGN: Twenty-seven women were scanned with (99m)TcO(4)(-) or (123)I(-) to assess NIS activity
in their metastases. An (131)I dosimetry study was offered to patients with I(-)-accumulating tumors. Selective down-
regulation of thyroid NIS was tested in 13 patients with T(3) and in one case with T(3) + methimazole (MMI; blocks I(-)
organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry.

RESULTS: I(-) uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show
NIS expression or activity. Thyroid I(-) uptakes were decreased to </=2.8% at 24 h in T(3)-treated patients and 1/100
normal with T(3)/MMI. Uptake (2.9%) was calculated in a peribronchial metastasis on (131)I dosimetry scans at 4 h
with disappearance of the signal by 24 h. We estimated a therapeutic dose of 3000 cGy could be achieved in this
metastasis with 100 mCi of (131)I if the tumor exhibited the same dynamics as the T(3)/MMI-suppressed thyroid.

CONCLUSIONS: This is the first article of in vivo, scintigraphically detected, NIS-mediated I(-) accumulation in human
BCM. T(3)/MMI down-regulation of thyroid NIS makes (131)I-radioablation of BCM possible with negligible thyroid
uptake and radiation damage.


The mammary gland iodide transporter is expressed during lactation and in breast cancer.
Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG,
Carrasco N.
Nat Med. 2000 Aug;6(8):871-8.
[abstract only]

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By
exploiting this activity, radioiodide has been used for decades with considerable success in the detection and
treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary
gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary
tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we
demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes
actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples
we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating)
samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter
may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the
diagnosis and treatment of breast cancer.

______________________________________________________________________________________________________
Cho

Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands.
Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WE Jr, Mazzaferri EL, Jhiang SM.
J Clin Endocrinol Metab. 2000 Aug;85(8):2936-43.

The observation that radioiodide uptake (RAIU) activity, mediated by the Na+/I- symporter (NIS), is significantly
increased in lactating breast suggests that RAIU and NIS expression in mammary gland are modulated by
hormones involved in active lactation. We showed that both the NIS expression level and RAIU in rat mammary gland
are maximal during active lactation compared to those in the mammary glands of virgin and pregnant rats as well as
the involuting mammary gland. In the lactating mammary gland, NIS is clustered on the basolateral membrane of
alveolar cells as a lesser glycosylated form than NIS in thyroid. The RAIU of lactating mammary gland was partially
inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of PRL release. These
findings suggest that RAIU and NIS expression in mammary gland are at least in part modulated by oxytocin and
PRL. Indeed, we showed that NIS messenger ribonucleic acid level was increased in a dose-dependent manner by
oxytocin and PRL in histocultured human breast tumors.

______________________________________________________________________________________________________
Clur

Di-iodothyronine as part of the oestradiol and catechol oestrogen receptor--the role of iodine, thyroid hormones and
melatonin in the aetiology of breast cancer.
Clur A.
Med Hypotheses. 1988 Dec;27(4):303-11. Review.

Hypothyroidism and low iodine intake may be important aetiological factors in oestrogen dependent tumours of the
breast, uterus and ovary. They are preventable risk factors. Iodine supplementation will hopefully lead to a decreased
incidence of these cancers in future generations.

The present author proposes that the tyrosyl residue in the hydrophobic oestrogen binding site of the oestrogen
receptor is post translationally modified to monoiodotyrosine and hence 3,3' di-iodothyronine monoamine (T2) by
peroxidase activity. He has previously proposed that various monoamine receptors are also T2 based. The densities
of these receptors are increased in hypothyroidism and they exert control over release of prolactin and other
hormones, including melatonin at multiple sites in the hypothalamic--pituitary axis. Melatonin is a metabolite of
serotonin and hence melatonin receptors may be T2 or rT3 based as well. These factors could be significant in the
aetiology of breast cancer as high prolactin and melatonin levels may be protective.

Oestrogen receptor density may be increased in hypothyroidism as is certain monoamine receptor density. This
would amplify the effect of high circulation oestrogen levels in hypothyroidism and may help explain why
hypothyroidism and low iodine intake are risk factors for breast, uterine and ovarian cancer.

______________________________________________________________________________________________________
Debski

Human breast cancer tissue expresses high level of type 1 5'-deiodinase.
Debski MG, Pachucki J, Ambroziak M, Olszewski W, Bar-Andziak E.
Thyroid. 2007 Jan;17(1):3-10.
[abstract only]

Type 1 5'-deiodinase is one of two isoenzymes that participate in conversion of prohormone thyroxine into
triiodothyronine (T3). A decrease in type 1 5'-deiodinase expression was observed in renal clear cell carcinoma,
thyroid cancer, and lung cancer. The aim of this study was to evaluate type 1 5'-deiodinase activity and mRNA level in
breast cancer tissue and non-cancerous surrounding breast tissue. Material was collected from 36 patients
undergoing radical mastectomy or local tumor resection. In all non-cancerous breast tissues, type 1 50-deiodinase
activity was found to be at a very low or immeasurable level, and type 1 5'-deiodinase mRNA was detected only in 2
out of the 36 samples. By contrast, 20 out of the 36 breast cancer tissues, mainly grades G1 and G2, expressed
abundant type 1 5'-deiodinase activity and/or a high mRNA level. Our data demonstrated the presence of type 1 5'-
deiodinase in well-differentiated breast cancer tissue. High enzymatic activity of type 1 50-deiodinase can potentially
lead to an increase in the production of T3, which may affect target gene transcription, including genes responsible
for energy expenditure, growth, differentiation, and proliferation.

______________________________________________________________________________________________________
Derry

Breast Cancer: The Iodine and Thyroid Connection
Derry D

Fibrocystic disease of the breast consists of small or large, sometimes painful lumps in women’s breasts. It varies
in the way it shows—not only in different women, but also because it changes from month to month in the same
women. Medical doctors generally believe that fibrocystic disease results from the excess number of cells that grow
in the breast during the menstrual cycle from the hormonal stimulation.

Since the number of cells increases in the breast during the cycle, some of the cells have to be removed to restore
the normal state each month. Iodine is the trigger mechanism that causes excess cells to disappear to complete
this normal process of cell death. Without enough iodine, the extra cells that develop during the menstrual cycle due
to the hormonal stimulation do not resolve back to the normal breast architecture. These leftover cells build up over
repeated cycles and cause the lumps, soreness, and larger lesions of fibrocystic disease.

However, while about 90 percent of North American women have fibrocystic disease, about 40 percent of these
women experience no symptoms. Their breasts may be normal to examination, but the disease may be only
microscopically detectable with a biopsy.

Enough iodine enables the excess cells to be cleared out, and the breast can return to its normal resting state as the
fibrocystic disease slowly disappears from the breast.

Fibrocystic disease over decades of hormonal stimulation eventually tends to cause some cells to change to cancer
cells. Lack of iodine causes fibrocystic disease, so women who have fibrocystic disease are susceptible to breast
cancer. Although breast scars from fluid leakage out of the cysts are often permanent, iodine given therapeutically in
the correct doses gradually gets rid of all fibrocystic disease except for the scars.

How much iodine is enough? It has been shown that daily doses of iodine above two to three milligrams per day
(about half a drop from a standard eyedropper) saturate the thyroid within a couple of weeks. At this point, the thyroid
gland stops taking up iodine. This means that at a dietary intake above two to three milligrams, all of the iodine goes
to all its other functions in the body, such as killing off abnormal cells.

Iodine remains the perfect antiseptic with the least side effects of all time. As a perfect antiseptic killing all single-
celled organisms, there has to be a common mechanism of a single element like iodine. In fact, the reaction of
iodine with tyrosine destroys the protein and consequently the cell itself. If, in vertebrates and multicellular
organisms, the tyrosine molecule is hidden from the surface when it is normally functioning, the iodine will not trigger
any apoptosis. However, during abnormal development, it could be that tyrosine or histidine molecules are slowly
exposed to the surface. Extracellular iodine bathing the cells could then trigger the apoptotic mechanisms.

The second phase of cancer spread involves thyroid hormone indirectly. The connective tissue barrier and function is
controlled and strengthened by adequate levels of connective tissue thyroid hormone. Thus thyroid hormone controls
the connective tissue barrier, and prevents the spread of cancer cells.

Iodine in adequate doses prevents the development of cancer cells, and adequate thyroid hormone in the connective
tissue prevents the spread.


Breast Cancer and Iodine: How to Prevent and How to Survive Breast Cancer  (Book)
David M. Derry, MD
Trafford Publishing, Victoria, Canada, 2001.

Iodine is the trigger mechanism for apoptosis (that natural death of cells) and the main surveillance mechanism for
abnormal cells in the body.  Iodine triggers the death of cells which are abnormal or which have normal programmed
death as part of their life cycle.  

This is part of a general thesis that iodine and thyroid hormone act as a team to provide a constant surveillance
against abnormal cell development, chemicals that are carcinogenic and the spread of cancer cells within the body.  

Iodine appears to have several more roles in the body.  Iodine protects against abnormal growth of bacteria in the
stomach (helicobacter pylori is the most clinically significant.)  Iodine can coat incoming allergic proteins to make
them non-allergic, which likely also applies to the internal equivalent called autoimmune disease.  Iodine binds softly
to the double and triple bond of lipids to protect these bonds while they are being transported to synaptic sites in the
brain and blood vessels of the body.  As well iodine in the stomach deactivates all biological and most chemical
poisons.  

All of these new proposed testable functions of iodine are discussed.  There is a discussion of the possible role of
iodine in evolution in relation to development of multi-cellularity and maturation of vertebrates.  

The general thesis of this took is that there is a specific dose of iodine intake above which it prevents several
disease processes including those related to fibrocystic disease and breast cancer.


Breast - Iodine - Thyroid Effectiveness
McLean C

Dr.  Derry's radical new thesis suggests a specific dose of the old- fashioned antiseptic, iodine, prevents many
diseases, including breast, prostate, ovarian and colon cancer.

I propose that...iodine and thyroid hormone act as a team to provide a constant surveillance against abnormal cell
development, chemicals that are carcinogenic, and the spread of cancer cells within the body," writes Dr. Derry, who,
in addition to holding an M.D., has a PhD in neurochemistry and is a former University of Toronto Medical Research
Council Scholar.  "Cancer grows so slowly when using iodine and thyroid hormone therapy that the cancer will not
affect the lives of the patients who have it.  The treatment is non-invasive, inexpensive and safe.

Dr.  Derry also credits iodine with several other roles in the body: It protects against abnormal growth of bacteria in
the stomach.  It detoxifies chemicals, food poisoning, snake venom, etc. It coats incoming allergic proteins to make
them non-allergic, and probably defuses autoimmune disease mechanisms in the same way.

The problem, according to Dr.  Derry, is the low dietary intake of iodine in the Canadian diet, particularly with iodized
salt intake being generally reduced since the 1950s, depriving people of "the most important element in the human
diet." What little iodine is consumed, is captured first by the "master gland," the thyroid, to produce thyroid hormone,
leaving little or none for other functions such as fighting cancer.

I believe that if the iodine intake of the nations were raised to levels above the saturation point of the thyroid," Dr.  
Derry writes, "there would be a precipitous drop in the cancer rate of the nation to levels similar to those of Japan.  
There, rates of breast, prostate and thyroid cancer are among the lowest in the world, and iodine intake is the highest
due to consumption of seaweed.

These levels of five to 10 mg.  of iodine daily can be easily reached with Lugol's [iodine] solution," he explains, "one
drop per day." Dr.  Derry recommends the drop of iodine each day be taken in a glass of juice to cover the mild taste.


Breast Cancer, Tamoxifen, Thyroid & Weight Loss  (With Dr. Derry)
Interview by Mary Shomon

I would like to tell you my thoughts on breast cancer and thyroid disease in an abbreviated form. Breast cancer takes
around 20-30 years to develop. The discovered lump represents the end stage of slow cancer progression over
decades. The longest period is the first phase of cancer development. This phase which is often called pre-
cancerous happens as as a normal cell is gradually turned into a cancer cell. These pre-cancerous lesions are
known as fibrocystic disease (lumpy, tender breasts) of the breast. (2-3,13-14) Most fibrocystic disease is benign,
harmless and has no consequences.

On the other hand, some more advanced forms of fibrocystic disease have clearly defined tendencies towards
breast cancer. So there are grades of fibrocystic disease with some of the cells looking more abnormal than in the
benign forms. The greater the difference in the cells from normal (abnormal) the greater chance of these cells
converting to a cancer cell over 10-20 years. So if you have fibrocystic disease still at the age of 45-55, you likely have
had this for many years. There maybe then a significant chance the cells may change into a cancer cell. The good
news is that it can be cleared up completely with a daily intake of iodine.(9)

If it is true there has been a general decrease in salt intake and thus iodine intake since the 1950s, there should
have been a general increase in the number of women with fibrocystic (lumpy) disease of the breast. But if as well
even lower iodine intake was occurring in the female population, worse forms of fibrocystic disease would occur
which are statistically directly related to breast cancer. The chances of getting breast cancer then go up considerably.
Now if we put this together with the incidence of breast cancer going from 1 in 23 in the mid 1960s to 1 in 8 currently
then it seems to fit together. Over the last 80 years hundreds of publications have confirmed statistical correlations
between the worse forms of fibrocystic disease of the breast and subsequent breast cancer. Unfortunately if you
have fibrocystic disease you really don't know what type you have without a biopsy. On the other hand if you take
iodine in adequate amounts daily all of the fibrocystic disease disappears so that you are essentially preventing
breast cancer from occurring. If a cancer has already started it is unlikely it will be stopped with the iodine at that
dose.

From my personal investigations cancer is roughly divided into two phases. The first part is the pre-cancerous phase
(before cancer) and involves the change of a normal cell into a cancer cell. This first phase of cancer development
takes about 10-30 years. Iodine in adequate doses stops and reverses this stage of the cancer process by causing
the natural death of abnormal cells (apoptosis). Iodine circulates throughout the body in the extracellular fluids found
between the cells of the body. If cell surface proteins have the amino acid tyrosine on the outside, the passing iodine
reacts with this tyrosine. This little reaction denatures the protein and thus kills the cell. It is implied all vertebrate cell
membranes do not have tyrosine on the portion of the protein sticking out into the extracellular fluid.

However, the intra membrane proteins may have tyrosine which is only exposed when the membrane is distorted by
abnormal cell development such as we see in the pre-cancerous forms of fibrocystic disease. This would then
expose the tyrosine to the iodine passing in the extracellular fluid. Again the iodine would denature the protein by
reacting with the tyrosine and thus kill off the cell. So thus we have surveillance system for removing abnormal cells
from our bodies. On the other hand low iodine intake allows cells to proceed and develop towards cancer. This is
more indirect because the gradual increase in abnormal cells are just not being eliminated from the body because
there is inadequate iodine to carry this out.

Once the cell has become a cancer cell then it can take two different turns. It can multiply and spread or it can
multiply and just stay where it is. The second is called carcinoma in situ. (cancer at the site) The second phase
(cancer multiplying and spreading) is the part we are all familiar with. Since on average breast cancer cells double
every 100 days, it takes 9 years before mammograms can pick it up and around 11 years before we find it ourselves.
(15)

This second clinical part of the cancer phase (the spreading) seems to be arrested by adequate levels of thyroid
hormone in all tissues. Thyroid hormone completely controls the connective tissue which forms a strong sieve-like
barrier to the passage of cancer cells trying to spread.(16-18) Low levels of thyroid hormone in the tissues
(especially connective tissues) promotes the spread of cancer cells. So the body cancer defense system has two
parts iodine for the first pre-cancer phase and thyroid hormone and iodine together for the second clinical phase.
There is some overlapping of these two defense systems. The excess iodine flows out in the urine. Of course,
because the iodine flows out in the urine it is preventing the development of abnormal cells in the bladder and kidney
system at the same time. This then prevents cancers developing there.

An adequate dose of iodine can be defined as more than 4 mg per day. Lugol's solution is an iodine-in-water
solution used by the medical profession for 200 years. One drop (6.5 mg per drop) of Lugol's daily in water, orange
juice or milk will gradually eliminate the first phase of the cancer development namely fibrocystic disease of the
breast so no new cancers can start. It also will kill abnormal cells floating around in the body at remote sites from the
original cancer. Of course this approach appears to work for prostate cancer as prostate cancer is similar to breast
cancer in many respects. Indeed, it likely will help with most cancers. Also higher doses of iodine are required for
inflammatory breast cancer. As well we know that large doses of intravenous iodine are harmless which makes one
wonder what effect this would have on cancer growth.


Topic: Disappearing Iodine Test
Interview of Dr David Derry by Mary Shomon

The "test" of putting iodine on the skin to watch how fast it disappears is not an indicator of anything. The iodine
disappearance rate is unrelated to thyroid disease or even iodine content of the body.(1-2) Meticulous research
by Nyiri and Jannitti in 1932 showed clearly when iodine is applied to the skin in almost any form, 50%
evaporates into the air within 2 hours and between 75 and 80 percent evaporates into the air within 24 hours. (1)
A total of 88 percent evaporates within 3 days and it is at this point that the evaporation stops. The remaining 12
percent that is absorbed into the skin has several fates. Only 1-4% of the total iodine applied to the skin is
absorbed into the blood stream within the first few hours. The rest of the iodine within the skin (8-11%) is slowly
released from the skin into the blood stream.

However Nyiri and Jannitti's findings that “The percentage of iodine penetration through the skin is the same,
irrespective of whether the cells have a high or low vitality, or are dead, and irrespective of the direction of
penetration" have important implications for iodine functions in the body, skin, pregnancy and fetus and also for
the therapeutic use of topical and oral iodine. Iodine would be the only compound of significance during early
pregnancy which can pass rapidly through all tissues of the fetus without the aid of any blood vessel or
lymphatic transport. It could be that not only does iodine control natural cell death (apoptosis) (5) in the fetus but
may also influences stem cell development.

Nyiri and Jannetti also mentioned iodine applied on the skin can be used to shrink swelling of the thyroid gland
(goiters). So even small amounts of iodine absorbed through the skin can have good effects on body organs.
From my own clinical experience, repeated application of iodine (Lugol’s) to the skin appears to cause
regeneration of the skin from the bottom up (Quiescent, stable or stem cell) (3) eventually sloughing the old
version of the skin off like a snake molting. If there was a pre-cancerous lesion on the old skin, it is replaced with
new skin minus the lesion. There does not seem to be any skin lesions which are not helped or cured by this
procedure. In some cases I found clinically obvious low thyroid conditions also needed to be treated to be more
effective. Minor lacerations and healing of surgical wounds respond well. If skin regeneration is from the bottom,
then there is little or no scar formation.

My parents’ generation tended to put tincture of iodine onto a fresh wound to prevent infection. This turns out to
be helpful but not the best way to use it. Besides it stung badly when applied. It is much more effective (and
doesn't hurt) to apply iodine repeatedly after a scab has been formed. The iodine put onto the scab helps to
organize total repair of the tissue. It is implied a similar approach could be taken to burns of all depths but at the
same time the physiology of burns suggest there is an acute lack of thyroid hormone. (3)

All pre-malignant lesions and many other oddities of the skin appear to respond to this regeneration process
triggered by topical iodine. I have mentioned previously a patient with a biopsy-proven breast cancer lesion (she
refused surgery because of previous cancer treatment) that was strongly fixed to the skin responding well to
topical iodine and ended up being a dimple on the breast three year later. (6)

It is my belief a water solution of iodine (like Lugol's) is an important therapeutic agent for skin. Because of its
effectiveness and the results, perhaps many skin diseases are related to local tissue areas of relative iodine
deficiency. Perhaps the most graphic lesions are the "keloid" (worm) incision scars formed after surgical
procedures. If the iodine intake and tissue levels are adequate, such as in Japan, keloid formation doesn't
happen (7). In addition, iodine's ability to trigger natural cell death (apoptosis) (5) makes it effective against all
pre-cancerous skin lesions and likely many cancerous lesions. The local site is replaced with normal skin.
However, even lesser doses of topical iodine seem to reverse the ominous appearance of skin lesions. Because
my older brother died of metastatic melanoma, my chances of getting a malignant melanoma are increased by
400 times. (8-9) Having grown up in Venezuela near the equator my sun exposure at a young age was far above
normal. So all suspicious lesions I notice are returned to normal with topical Lugol's...."

Some of our recent serious skin diseases such a "flesh-eating disease" should respond quickly to topical iodine
treatment practiced by Fanny. Or, for another example, iodine put onto a mosquito bite would kill all bacteria and
viruses at the site of the bite within 10-30 seconds making it impossible for any virus or bacteria to multiply and
get started --such as in West Nile Fever. Naturally, this applies to tic bites (Lyme's disease) as well. For many
decades in the 1800s people carried around little bottles of iodine around their necks to use on all occasions.
People in mosquito and tic infested areas should think of doing this again. (8) In addition, it has been forgotten
vaporized iodine rapidly kills air borne viruses such as polio and SARS viruses.. Used extensively in the forties
and fifties it may be of use to explore this approach again....

Of course, since large doses of iodine are tolerated intravenously without side effects, it has yet to be explored
what help this may have for many cancer patients or even other diseases.