title: Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis.
abstract: Long term exposure to estrogens is associated with an increased risk of breast cancer. The precise mechanisms responsible for estrogen mediated carcinogenesis are not well understood. The most widely accepted theory holds that estradiol (E(2)), acting through estrogen receptor alpha (ERα), stimulates cell proliferation and initiates mutations arising from replicative errors occurring during pre-mitotic DNA synthesis. The promotional effects of E(2) then support the growth of cells harboring mutations. Over a period of time, sufficient numbers of mutations accumulate to induce neoplastic transformation. Laboratory and epidemiological data also suggest that non-receptor mediated mechanisms resulting from the genotoxic effects of estrogen metabolites are involved in breast cancer development. This manuscript critically reviews existing data implicating both ER-dependent and -independent mechanisms. The weight of evidence supports the possibility that both mechanisms are involved in the carcinogenic process. In addition, estrogen metabolites likely modulate stem cell functionality and cancer progression. The roles of ER dependent and independent actions in the carcinogenic process are pertinent to the consideration of breast cancer preventative agents as anti-estrogens block only receptor mediated pathways whereas the aromatase inhibitors block both.
authors.affiliation: University of Virginia, Department of Medicine, Division of Endocrinology & Metabolism, Charlottesville, VA 22908, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: James D
authors.initials: JD
authors.lastname: Yager
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Eldon R
authors.initials: ER
authors.lastname: Jupe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D009153:Mutagens; D011960:Receptors, Estrogen; D004958:Estradiol