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Medical Hypothesis: Bifunctional Genetic-Hormonal Pathways

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Medical Hypothesis: Bifunctional Genetic-Hormonal Pathways Medical Hypothesis: Bifunctional screening practices do not explain geo- graphic variations in prevalence of the dis- Genetic-Hormonal Pathways ease (1-4). Inherited germ cell mutations occur in about 5% of all cases and in about to Breast Cancer 30% of cases under 40 years of age (3-6). The common tie linking most of the Devra Lee Davis,1 Nitin T. Telang," 2 Michael P. Osborne,2 established risk factors, aside from these and H. Leon Bradlow2 mutations, is greater cumulative exposure to bioavailable 17,-estradiol (E2) (4, 7-11). 1World Resources Institute, Washington, DC; 2Strang Cancer Research Bioavailable E2 is defined as a free hor- Laboratory, The Rockefeller University, New York, New York mone not bound to steroid hormone- binding globulin (SHBG) or weakly bound As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all to albumin (9-12). Women with elevated breast cancer, most cases involve acquired somatic perturbations. Cumulative lifetime exposure levels of bioavailable E2 have a 2- to 4-fold to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based excess risk of breast cancer (10). Bio- on a series of recent experimental and epidemiologic findings, we hypothesize that the multistep available E2 can diffuse into cells and sub- process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, sequently be taken into the nucleus where including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are it can bind to the estrogen receptor (ER). defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, The hormone also can be converted in the through genetic or hormonal paths, depending on the periods and extent of exposure. As for active genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two cytoplasm into other biologically distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly metabolites and free radicals (4,7). In bind with endogenous hormone or growth factor receptors affecting cell proliferation or addition, other hormones, such as andro- compounds can modify breast cell proliferation altering the formation of hormone metabolites that gens and progestagens, can influence the influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as production and metabolism of E2 indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, (4,9-12). The hormone-SHBG complex and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal bound to the cell surface receptor induces microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers cAMP-mediated phosphorylation (12). 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 Medical Hypothesis 105(Suppl 3):571-576 (1997) We have previously suggested that Key words: estradiol metabolism, genetic and hormonal mechanisms, breast cancer, compounds functioning as xenoestrogens xenohormones, xenoestrogen, environment affect the rate and type of estradiol metabo- lites formed. Xenoestrogens may also bind directly with the ER to modulate breast cell proliferation and thereby influence the Introduction development of breast cancer and other hormonally mediated diseases (9,11,12). In As the most common cancer among half of all women die from to breast cancer this report we expand the hypothesis to women in modern societies, breast cancer by one decade after diagnosis (1-3). include a more detailed consideration of is a complex and important disease. The About one-third of all cases of breast possible genetic-hormonal-environmental average patient who dies with the disease cancer can be attributed to recognized risk interactions (3,4), including the complex loses about two decades of life, so that factors. Neither changes in established risk relationship among estrogens, androgens, nearly 2 million women-years of life are factors nor screening practices completely their antagonists, and other hormones in lost annually to breast cancer in the United account for the persisting 1% annual breast cancer development. States and Europe (1). Although about increase in the incidence of breast cancer. Based on recent experimental and 87% of all cases survive for 5 years, nearly Similarly, changes in risk factors or in epidemiologic findings in this laboratory and elsewhere (4,9,11,13), we hypothesize that prenatal, adolescent, or midlife expo- sure to endogenous endocrine agents, xeno- This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and hormones, or their metabolites can have Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 2 August 1996. bifunctional effects on the risk ofdeveloping The laboratory research programs have been funded in part by National Institutes of Health grants CA44741 breast cancer. and CA 29502, Department of Defense grant DAMD 1 7-94-J-4208, and philanthropic support to the Strang We also hypothesize that some xeno- 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. hormonal exposures can, through redox Address correspondence to Dr. D.L. Davis, World Resources Institute, 1709 New York Avenue, cycling between estrogens and their corre- Washington, DC 20006. Telephone: (202) 638-6300. Fax (202) 638-0036. E-mail: [email protected] sponding quinones, yield reactive oxygen Abreviations used: ATM, ataxia telangiectasia, mutated; DMBA, 7,12-dimethylbenz[a]anthracene; E2, 17,B species that can cause structural oxidative estradiol; ER, estrogen receptor; Fapy-A, 4,6-diamino-5-formamidopyrimidine; -OH, hydroxyl; 2-OHEj, 2-hydrox- yestrone; 16a-OHE1, 16a-hydroxyestrone; PI-3-kinases, phosphatidylinositol-3-kinases; SHBG, sex damage to DNA and increase rates of oxida- hormone-binding globulin. tive DNA base modifications (7,8,14-16). Environmental Health Perspectives * Vol 105, Supplement 3 * April 1997 571 DAVIS ET AL. Lipid oxidation products may also function carcinogenesis and its prevention. IN4aturally effects on preinitiated cells via hormone as endogenous DNA damaging-agents occurring or synthetic xenohormoines may and growth factor receptors or via intercel- (17). In addition, other types of reactive affect the process of tumorigenic ttransfor- lular gap junctional communication. These functions, such as methylation or phospho- mation at both genotoxic (initiatiional) or indirect effects predominantly operate dur- rylation, can affect key functional regions epigenetic (postinitiational) levels. Central ing the postinitiational (promotional) of DNA, induding cell cycle genes critical to the bifunctional effect of bioavaiilable E2 events of carcinogenic transformation. for cell proliferation, development, and is its enzymatic conversion to produicts with Beneficial xenoestrogens, such as growth. Exposure to xenohormones distinctive biological activity. The lmicroso- genistein and other bioflavonoids that through diet, pharmaceuticals, and envi- mal enzymes, aromatase, 17p-oxicioreduc- occur in vegetables, fruits, and grain prod- ronmental chemicals can alter the tase and steroid hydroxylases Cyp450 lAl, ucts, may reduce aberrant breast cell prolif- parenchymal environment, either by pro- 1A2, iBi, and 2B2 are essential enzymes eration and inhibit angiogenesis, and may moting already initiated breast cells into for steroid hormone metabolism (4,7-9, increase DNA repair processes and enhance relatively rapid proliferation or by imped- 11,13). The metabolites themselves or their cytodifferentiation and apoptosis. Some ing such growth, if the xenohormones are oxidative products may directly induce phytoestrogens such as genistein also antioxidants, hormone antagonists, or genotoxic DNA damage and modu lation of influence aberrant cell proliferation. At the antiangiogenics (18). oncogene, tumor suppressor gene, or cell- pharmacological levels these compounds Figures 1 to 3 show the impact of cycle control gene expression. Addiitionally, operating via receptor-independent mecha- steroid hormones on interacting genetic hormones, their metabolites, anid xeno- nisms may inhibit kinases and DNA and hormonal pathways critical for breast estrogens may exert epigenetic, paracrine topopisomerases and thereby affect other intracellular biochemical targets (14-16). About 15% of women who are carriers Xenohormones, Xenohormones, of mutated BRCAI apparently do not endogenous hormones endogenous hormones develop breast cancer (5,6). In these cases, beneficial xenohormones or other exogenous factors may play a positive role by promot- Cyp450-dependent 17p-oxidoreductase Cyp450-dependent 17p-oxidoreiductase ing enzymatic detoxification of potential aromatase aromatase carcinogens, DNA repair processes, or Total bioavailable estradiol Total bioavailable estradiol E2 DEl E2 I D E ] rE2 * oEl_ Cyp450-dependent hydroxylases Cyp450-dependent hydroxylases 16a-OHE1, 4-OHE1, 4-OHE2 2-OHE1, 2-OHE2, 16a-OHE1, 4-OHE1, 2-MeOHE, 4-OHE2 Genotoxic DNA damage (E2 antagonists) (E2 agonists) l \ I~~~~~~~~~~ DNA Altered expression of cell
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