Tamoxifen Versus Aromatase Inhibitors for Breast Cancer Prevention
Vol. 11, 925s–930s, January 15, 2005 (Suppl.) Clinical Cancer Research 925s Tamoxifen versus Aromatase Inhibitors for Breast Cancer Prevention Wei Yue,1 Ji-Ping Wang,1 Yuebai Li,1 estrogen receptor (ER) a or h and stimulate the transcription of Wayne P. Bocchinfuso,4 Kenneth S. Korach,2 genes involved in cell proliferation (refs. 8, 9; Fig. 1, left). With each cycle of new DNA synthesis during mitosis, the chances for Prabu D. Devanesan,3 Eleanor Rogan,3 3 1 error in DNA replication without adequate repair increase. As the Ercole Cavalieri, and Richard J. Santen proliferative process continues, several mutations accumulate 1University of Virginia Health System, Charlottesville, Virginia; (8–11). When these mutations disrupt critical regions required 2 National Institute of Environmental Health Services, Research Triangle for cellular proliferation, DNA repair, angiogenesis, or apoptosis, Park, North Carolina; 3Eppley Institute, Omaha, Nebraska; and 4PPD Discovery, Morrisville, North Carolina neoplastic transformation results (12). An alternative hypothesis, which has remained controver- sial, is that estradiol can be converted to genotoxic metabolites ABSTRACT and directly damage DNA (refs. 10, 11, 13, 14; Fig. 1, right). Long-term exposure to estradiol is associated with an The putative genotoxic pathway involves cytochrome P450 increased risk of breast cancer, but the mechanisms 1B1, which catalyzes the hydroxylation of estradiol to 4-OH- responsible are not firmly established. The prevailing theory estradiol. This compound is then further converted to the postulates that estrogens increase the rate of cell prolifera- estradiol-3,4-quinone, which can bind covalently to guanine or tion by stimulating estrogen receptor (ER)–mediated tran- adenine, resulting in destabilization of the glycosyl bond that scription, thereby increasing the number of errors occurring links these purine bases to the DNA backbone (Fig.
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