Soy Risks for Breast Cancer

Similarity of Estrogenic Effects Compared To Human and Synthetic Estrogen

Compiled by: Jane Smith

Introduction

The relationship between soy estrogen and breast cancer can be easier to understand when it is placed in a broader context.

The citations below give some reported findings about the development of breast cancer and how supplemental estrogen can be a risk factor, whether produced by the human body, manufactured as a synthetic chemical, or consumed from a plant source.

This list is not intended to be complete, but rather to show an overall pattern. A researcher specializing in this field might prepare a more thorough list, but every report is accurate and credible, from scientifically accepted sources.

No one can claim that breast cancer or its mechanisms are fully understood. There may also be conflicting reports regarding some of the citations listed below. We already have enough information, however, that a reasonable, responsible person would want to exercise caution.

The citations are broken into three main groups, corresponding to the way many scientists see the pattern of development.

• Breast Cell Proliferation - Various studies have found this to occur prior to the appearance of tumors. There is some indication that it may lead to the tumors, when the excessive proliferation of cells includes some aberrations and DNA errors.
• Appearance of Tumors - This is the point at which tumors are detected that have the typical characteristics - such as MCF-7 cells.
• Growth of Tumors - This represents the phase when tumor size and progression can be measured.

In each group, the reports show essentially the same types of harmful effects, regardless of the source of estrogen supplement, for both humans and research animals. The effects were also detected in males as well as females, suggesting the importance of the incremental estrogen, rather than the natural levels in the human body.

At the end of this document you will find additional references listed in the notes section for general background on estrogen and breast cancer.

Background

History

"The impact of estrogen on breast cancer has been known for more than 100 years. One of the initial therapies for advanced breast cancer was removing the ovaries (which normally produce estrogen in premenopausal women). The percentage of breast cancers that are estrogen-receptor positive varies a little bit, depending on age. In premenopausal women, it's probably about 50 percent. In women after menopause, it can be as high as 70 percent."

D. Lawrence Wickerham MD, Associate Chairman of the National Surgical Adjuvant Breast Project, and Associate Professor of Human Oncology at Drexel University. (Interview for ABC News Published on: September 4, 2003)

Types of Estrogen

"Estrogen is not one hormone, it is the name of a group of hormones. There are three principle forms of estrogen found in the human body estrone, estradiol and estriol, also known as E1, E2 and E3 respectively.

There is also a group of compounds called phytoestrogens, generally found in food, which can have "estrogen like" effects in the body. Estradiol (E2) is the primary estrogen produced by the ovaries. Estrone (E1) is formed from estradiol. It is a weak estrogen and is the most abundant estrogen found in the body after menopause. Estriol (E3) is produced in large amounts during pregnancy and is a breakdown product of estradiol. Estriol is also a weak estrogen and may have anti-cancer effects. Before menopause estradiol is the predominant estrogen. After menopause estradiol levels drop more than estrone so that now estrone is the predominant estrogen."

Mechanics

This is a high level description of how estrogen interacts with the estrogen receptor to initiate the creation of new cells. This is the 'classical' mechanism; scientists also see evidence of other processes.

"Estrogens are also involved in the development of breast cancers. In the absence of hormone, the [Estrogen Receptor] resides in the nucleus of target cells, where it is associated with the heat-shock proteins hsp90 and hso59. The binding of [Estrogen] to [the Estrogen Receptor] is followed by a conformational change leading to a dissociation of the receptor from the heat-shock proteins, formation of stable receptor dimers, and subsequent interaction with the [Estrogen Response Element]. Although the precise mechanism remains to be determined, the agonist bound [Estrogen Receptor] can recruit accessory proteins that permit the receptor to activate the transcriptional apparatus."

Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. Nikov GN, Hopkins NE, Boue S, Alworth WL.

Environ Health Perspect 108:867-872 (2000). [Online 1 August 2000]

Studies: Breast Cell Proliferation

Human Estrogen and Cell Proliferation

Supplemental estrogen increases cell proliferation, increases cancer risk.

"The administration of supplemental E2 resulted in proliferative effects... leading to increased proliferation and cellularity, this result demonstrates that estrogen can provide a proliferative signal to the mammary epithelium and increase the number of target cells..."

"E2 given to mice ovariectomized at 8-weeks of age induced significantly more high-grade MIN lesions and invasive carcinomas than untreated ovariectomized mice. "

"There is strong evidence that a similar phenomenon occurs in human breast cancer, where higher density of breast epithelium is associated with an increased risk of breast cancer. Hormone replacement therapy is associated with increased breast density which may be part of the mechanism of hormone replacement therapy in elevating the risk of developing breast cancer".

Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptor alpha expression during tumor progression.

Cancer Res. 2000 Dec 15;60(24):6901-10.

Synthetic Estrogen and Cell Proliferation

Barbara Seaman, who is an author on women's health issues, especially estrogen supplements, described how researchers in 1938 observed the effects of synthetic estrogen on breast growth. This is from an interview with webmd and refers to the potent and infamous synthetic estrogen DES.

"Dodds knew that his product might cause cancer, because the men in his laboratory who handled the stilbestrol powder were growing breasts. Their suspenders were ballooning out over their shirts. He sent the powder to cancer researchers who learned that it did cause reproductive cancers in female and male laboratory animals. Dodds and most cancer researchers urged that estrogen products should not go into general use, but just be reserved for cases where there was a severe need"

Soy Estrogen and Cell Proliferation

Soy estrogen modified the structure of the breast

"In contrast to our expectations and evidence in the literature of a protective effect of dietary phytoestrogens..."
"...postnatal genistein treatment...induced profound alterations in mammary gland morphology...consistent with prolonged estrogen exposure."

Mammary Gland Morphology in Sprague-Dawley Rats following Treatment with an Organochlorine Mixture in Utero and Neonatal Genistein.
Toxicol Sci. 2004 Jan;77(1):91-100. Epub 2003 Sep 26.

Soy Estrogen and Cell Proliferation

Two weeks of dietary soy produced measurable cell growth.

"The proliferation rate of breast lobular epithelium significantly increased after 14 days of soy supplementation when both the day of menstrual cycle and the age of patient were accounted for. Progesterone receptor expression increased significantly in the soy group. Short-term dietary soy stimulates breast proliferation"

Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.
Am J Clin Nutr. 1998 Dec;68(6 Suppl):1431S-1435S.

Soy Estrogen and Cell Proliferation

Estrogenic effects from a high-soy diet included nipple discharge, breast enlargement and decreases in testosterone in an experiment conducted on a group of men at the University of North Carolina.

This has not been published, but was reported by the The Washington Post, May 4, 2004, which treated it as a joke.

Studies: Appearance of Tumors

Human Estrogen and Appearance of Tumors

Inducing breast cancer in various animals for research purposes.

"Lacassagne was the first to show that injections of estrogens, either at birth or at an early age caused mammary tumors to develop with the same frequency in male and female mice. Thereafter numerous reports of estrogen-induced tumors appeared and many rodent tumor models have been introduced. The ACI rat differs from earlier animal models and it is particularly valuable because estrogen-induced mammary tumorigenesis can be achieved within a relatively short period of time (16-18 weeks) following chronic exposure to very low amounts of E2."

Catechol estrogen formation in liver microsomes from female ACI and Sprague-Dawley rats: comparison of 2- and 4-hydroxylation revisited.
Carcinogenesis. 2002 Aug;23(8):1369-72

Mesia-Vela S, Sanchez RI, Li JJ, Li SA, Conney AH, Kauffman FC.

Human Estrogen and Appearance of Tumors

French researcher injected human estrogen and induced tumors.

Apparation de cancers de la mamelle chez la souris male, soumise a des injections de falleculine.
Compt Rend Acad Sci. vol 195. Lacassagne 1932

Synthetic Estrogen and Appearance of Tumors

Researchers induced breast cancer in nearly all animals within a few weeks by administering a single dose of a synthetic estrogen. Nature. Vol 189 1961 Huggins etc e.g. cited in American Association for Cancer Research

Soy Estrogen and Appearance of Tumors

In this study the soy estrogen induced a different type of tumor – not breast cancer. But the study is included here to show that researchers have noted similarities between soy estrogen and synthetic estrogen.

"...we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure… At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation."
Uterine adenocarcinoma in mice treated neonatally with genistein.
Newbold RR, Banks EP, Bullock B, Jefferson WN. Cancer Res. 2001 Jun 1;61(11):4325-8.

Soy Estrogen and Appearance of Tumors

Soy estrogen increased the likelihood of tumerogenisis.

"In mice exposed during adult life, isoflavones and flaxseed did not protect but rather stimulate the onset of mammary adenocarcinoma development"

Soy-derived isoflavones and a high-fat Western diet enhance spontaneous mammary tumor development in TG.NK mice

M. Luijtena, A. Rønfeldt Thomsenc, J. van den Berga, Piet Westera, A. Verhoefa, N. J. D. Nagelkerkeb, A. Samaletdind, R. Takkinend, H. Adlercreutzd, A. Piersmaa,I. K. Sørensenc, G. N. Rao, H. J. van Kranenaand C. F. van Kreijla

Authors represented national labs in Finland, Denmark, Netherlands, and the US.

Presented at Karlsruhe Congress 2003 Phytoestrogens Benefits and Risks for Human Health

Studies: Growth of Tumors

HRT Estrogen (various) and Growth of Tumors

HRT study involving several forms of estrogen supplements given to women with breast cancer was stopped prematurely due to the number of new breast cancer incidents in the group.

"This report details findings in a Scandinavian study of HRT, the HABITS (Hormonal Replacement Therapy After Breast Cancer Is It Safe?) Trial. The form of HRT (continuous combined, sequential, estrogen only) did not appear to be a significant factor. The HABITS trial was ended prematurely because of an unacceptably high risk of breast cancer in women with a history of breast cancer who received HRT. Actively treated women have been advised to discontinue HRT and to take the most effective nonhormonal medication."

HABITS (Hormonal Replacement Therapy After Breast Cancer Is It Safe?): A randomized Comparison Trial Stopped.
Obstet Gynecol Surv.2004 Jun; 59 (6):442-443

Soy Estrogen and Growth of Tumors

Two French doctors indicate that giving soy estrogen to women being treated for breast cancer will promote tumor growth. They argue that the soy estrogen will overcome the effects of Tamoxifen, a drug administered to stop tumor progression.

"To the Editor: The study of the treatment of hot flashes in breast cancer survivors presented by Quella et al in the March 2000 issue of the Journal of Clinical Oncology, testing 150 mg of isoflavones daily versus placebo in a double-blind randomized cross-over trial, is interesting in that it shows that there is no difference between treatment groups. Nevertheless, we would like to draw the attention to the following point: in this study, the concurrent use of tamoxifen or raloxifene was permitted, provided it had started at least 4 weeks before inclusion of patients in the study. Thus 68% of patients in each group were receiving concurrently an adjuvant endocrine therapy regimen.

What is the rationale for treating patients who are receiving adjuvant endocrine treatment with phytoestrogens? Genistein, which is the principal isoflavone in the tablets prescribed, is considered a weak estrogen, with binding affinity to the receptor and activity 20-fold less than that of estradiol. At the doses given in the study by Quella et al, genistein concentrations in the plasma would be between 0.1 to 3 µmol/L. Given alone at these concentrations, genistein has an estrogen-agonist effect on breast cancer cells. Adjuvant endocrine treatment of breast cancer with tamoxifen leads to similar plasma concentrations of this drug. Given the high affinities of tamoxifen and of its 4-OH metabolite to the estrogen receptor, the individual effects of genistein and tamoxifen would be minimized if they were administered simultaneously. Today, we know that there are two types of estrogen receptors, estrogen receptor alpha and estrogen receptor beta (ERΒ), with overlapping but distinct distribution in different tissues. According to Kuiper et al, genistein has a higher binding affinity to ERΒ than to estrogen receptor alpha, whereas tamoxifen has an equivalent affinity to each of these receptors. There are no reliable data on the actual concentrations of both targets receptors and administered compounds in the various target tissues. Finally, genistein seems to be only a partial agonist for ERΒ.

The prescription of phytoestrogens together with adjuvant endocrine treatment poses, in our opinion, two problems: (1) in the breast, by competing with tamoxifen or raloxifene as it does in vitro, it could diminish the efficacy of the adjuvant treatment, and (2) in the CNS, tamoxifen or raloxifene could diminish the binding of genistein to estrogen receptors and its estrogen-agonist activity, which could explain the negative results of the study by Quella et al.

Considering the present knowledge of the molecular mechanisms underlying the effects of phytoestrogens and tamoxifen (or raloxifene), their simultaneous administration after breast cancer should be envisaged only in randomized trials testing the in vivo impact of the association not only on climacteric symptoms but also on the efficacy of adjuvant breast cancer treatment."

Comment: Phytoestrogens and Adjuvant Endocrine Treatment of Breast Cancer
Pascale This, Henri Magdelenat Institut Curie Paris, France 2000

Soy Estrogen and Growth of Tumors

Soy estrogen caused existing tumors to grow even when a leading breast cancer drug Tamoxifen had been given.

"Dietary genistein negated/overwhelmed the inhibitory effect of TAM on MCF-7 tumor growth, lowered E2 level in plasma, and increased expression of E-responsive genes (e.g., pS2, PR, and cyclin D1). Therefore, caution is warranted for postmenopausal women consuming dietary genistein while on TAM therapy for E-responsive breast cancer."

Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice.

Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Cancer Res. 2002 May 1;62(9):2474-7.

Soy Estrogen and Growth of Tumors

Soy diets increased tumor growth - more soy produced larger tumor growth.

"Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm). Expression of pS2 was increased in tumors from animals consuming dietary genistein (150 and 300 ppm). Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent manner.

These data indicate that dietary soy isolates containing increasing concentrations of genistein and casein-based diets containing equalized concentrations of genistein act in a dose-dependent manner to stimulate growth of human estrogen-dependent breast cancer cells transplanted into athymic mice.

We believe the low endogenous estrogen environment created in this model by ovariectomizing the mice affords genistein the opportunity to be a significant source of estrogenicity in these animals and, hence, allows for the compound to stimulate the growth of these tumors. Therefore, if a postmenopausal woman with low endogenous E2 levels has an existing estrogen-dependent breast tumor it is also possible that consumption of dietary genistein from various food sources including soy protein isolate may produce sufficient plasma levels of genistein to result in enhanced estrogen-dependent tumor growth as observed in athymic mice.

...for the subgroup of postmenopausal women who have or are at high risk of developing breast cancer there is need for additional consideration into the possibility of enhancing estrogen-dependent tumor growth by consumption of isoflavone containing products."

Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner.
Allred CD, Allred KF, Ju YH, Virant SM, Helferich WG. Department of Food Science and Human Nutrition, University of Illinois, Urbana, Illinois 61801, USA.
Cancer Res. 2001 Jul 1;61(13):5045-50.

Soy Estrogen and Growth of Tumors

Experiments with various forms of soy products showed risk in all of them. The soy-free diet of the negative control group had the best results.

"Products investigated included soy flour, two crude extracts of soy, a mixture of isoflavones, and genistin in pure form. Tumors in the negative control animals regressed throughout the study while the tumors in the soy flour fed animals remained basically the same size (neither grew nor regressed). In animals consuming [all other forms of soy] tumor growth was stimulated when compared to animals consuming a control diet devoid of soy. These same dietary treatments resulted in increased cellular proliferation."

Soy processing influences growth of estrogen-dependent cancer tumors in mice.
Carcinogenesis, 2004 May 6 [Epub ahead of print]

Summary

Within each group, the reports parallel each other. They show essentially the same types of harmful effects, regardless of the source of estrogen supplement, for both humans and research animals. The effects were detected in males as well as females, suggesting the importance of the incremental estrogen, rather than the natural levels in the human body. Although scientists are still working in this area, there is already enough information that many women may prefer not to wait. Many may prefer to err on the side of caution by looking to alternatives other than increasing their exposure to supplementary estrogen, including phytoestrogens contained in dietary soy.

A support group for DES victims, in newsletter, made a telling observation when they noted the study by Newbold et al reporting that soy estrogen had produced effects similar to those of DES.

"[the study] confirms once again that estrogens at the wrong time can have extremely adverse effects, no matter whether they are from natural sources, like soy, or synthetic sources like DES"

DES Action Ireland Newsletter Winter 2001

Notes

See also

Are all estrogens the same? Coelingh Bennink HJ. Pantarhei Bioscience, Institute for Clinical Concept Research in Reproductive Medicine, Pantarhei Bioscience, Zeist, The Netherlands. hcb@pantarheibio.com Maturitas. 2004 Apr 15;47(4):269-75.

"This paper focuses on the question whether different estrogens (E) have different qualitative pharmacodynamic effects when used by women for contraception, Hormone Replacement Therapy (HRT) or prevention of osteoporosis. In this context estrogens have been defined as the estrogen agonists estradiol (E2), estrone (E1), estriol (E3), conjugated equine estrogens (CEE), diethylstilbestrol (DES) and ethinylestradiol (EE). Selective Estrogen Receptor Modulator's (SERM's) have been excluded from this analysis primarily because of lack of comparative (clinical) data with estrogen agonists. A major problem when addressing the issue of comparability of estrogen agonists is the lack of data from head-to-head estrogen-only comparative studies. Comparative studies have been performed almost exclusively with estrogen agonists combined with a series of different progestogens (P), that have been added to protect the uterus from endometrial hyperplasia. Since progestogens are known to exhibit different intrinsic pharmacodynamic properties and interactions with estrogens, it is impossible to judge which role the estrogen plays when qualitative differences between different combined E/P preparations are observed. In summary, no convincing evidence has been found that the estrogens mentioned differ qualitatively. Obviously quantitative differences are present due to differences in e.g. receptor affinity, metabolism (half life) and route of administration (transdermal/vaginal)"

Updated September 29, 2005

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