title: Estrogen metabolites and breast cancer.
abstract: Epidemiologic studies link several factors related to estrogen production in women to an increased risk of breast cancer. These include early menarche, late menopause, obesity, use of post-menopausal hormone therapy, and plasma estradiol levels. Two possible mechanisms have been proposed to explain the increased risk: (1) estrogen receptor (ER) mediated stimulation of breast cell proliferation with a concomitant enhanced rate of mutations and (2) metabolism of estradiol to genotoxic metabolites with a resulting increase in DNA mutations. The metabolism of estradiol can cause DNA damage in two ways: (a) formation of estradiol-adenine - guanine adducts which are released from the DNA backbone leaving depurinated sites which undergo error prone DNA repair and mutations and (b) generation of oxygen free radicals resulting from redox cycling of 4-OH estradiol to the 3-4 estradiol quinone and back conversion to 4-OH estradiol. If one or both pathways are operative, sufficient numbers of mutations accumulate over a long period of time to induce neoplastic transformation. Our studies are based on the hypothesis that both receptor-mediated and genotoxic pathways contribute to breast cancer. We initially demonstrated that MCF-7 breast cancer cells and normal breast tissue in aromatase transfected mice contain the enzymes necessary to convert estradiol to the estradiol DNA adducts. We then utilized a highly reductionist model to separately analyze the effect of estrogen receptor alpha (ER) on tumor formation and the effects of estrogen depletion by castration in ER knock out/Wnt-1 (ERKO/Wnt) transgenic animals to assess the effects of estradiol in the absence of an ER. Estradiol was added back in castrate ERKO/Wnt animals to determine if Koch's postulates could be fulfilled to increase the incidence of cancer with administration of exogenous estradiol. Finally, we assessed the effects of an aromatase inhibitor on tumor incidence in non-castrate, ERKO/Wnt animals. The studies demonstrated the conversion of estradiol to genotoxic metabolites in breast tissue. In addition, knockout of ERα caused a reduction in incidence of tumor formation and a delay in the occurrence of those that formed. Oophorectomy further reduced the incidence of tumors and delayed their onset whereas estradiol add-back returned the incidence rate to that observed before oophorectomy. The aromatase inhibitor, letrozole, delayed the onset of tumor formation. Taken together, these data support a role for estradiol metabolism as one of the components in the development of experimental breast cancer.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Sciences System, PO Box 801416, Aurbach Medical Research Building, Charlottesville, VA 22908-1416, United States. Electronic address: rjs5y@virginia.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Sciences System, PO Box 801416, Aurbach Medical Research Building, Charlottesville, VA 22908-1416, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Sciences System, PO Box 801416, Aurbach Medical Research Building, Charlottesville, VA 22908-1416, United States.
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D006801:Humans; D061986:MCF-7 Cells / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011960:Receptors, Estrogen / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011960:Receptors, Estrogen; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D001141:Aromatase
keywords: Adducts; Aromatase; Breast cancer; Estrogen; Genotoxic; Metabolites