Medical Hypothesis: Bifunctional Genetic-Hormonal Pathways
to Breast Cancer

Devra Lee Davis,¹ Nitin T. Telang,^1,2 Michael P. Osborne,² and H. Leon Bradlow²

¹World Resources Institute, Washington, DC; ²Strang Cancer Research Laboratory, The Rockefeller University, New York, New York

Abstract

As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all breast cancer, most cases involve acquired somatic perturbations. Cumulative lifetime exposure to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based on a series of recent experimental and epidemiologic findings, we hypothesize that the multistep process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, through genetic or hormonal paths, depending on the periods and extent of exposure. As for genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly bind with endogenous hormone or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormone metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailable estradiol, and free radical generators can enhance cancer detection and prevention. -- Environ Health Perspect 105(Suppl 3):571-576 (1997)

Key words: estradiol metabolism, genetic and hormonal mechanisms, breast cancer, xenohormones, xenoestrogen, environment

This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 2 August 1996.

The laboratory research programs have been funded in part by National Institutes of Health grants CA44741 and CA 29502, Department of Defense grant DAMD 17-94-J-4208, and philanthropic support to the Strang Cancer Prevention Center and to the World Resources Institute from Wallace-Global and the Jennifer Altman Fund.. The authors acknowledge the excellent editorial assistance of K.J. Brady.

Address correspondence to Dr. D.L. Davis, World Resources Institute, 1709 New York Avenue, Washington, DC 20006. Telephone: (202) 638-6300. Fax (202) 638-0036. E-mail: devra@wri.org

Abreviations used: ATM, ataxia telangiectasia, mutated; DMBA, 7,12-dimethylbenz[a]anthracene; E₂, 17ß-estradiol; ER, estrogen receptor; Fapy-A, 4,6-diamino-5-formamidopyrimidine; ^-OH, hydroxyl; 2-OHE₁, 2-hydroxyestrone; 16-OHE₁, 16-hydroxyestrone; PI-3-kinases, phosphatidylinositol-3-kinases; SHBG, sex hormone-binding globulin.

Last Update: April 10, 1997