Resistance to Antiestrogens

Discovery of the estrogen receptors (ERs) has been critical for the development of endocrine therapy in breast cancer. Expression of ER-?, the predominant isoform, in breast tumors of both pre- and postmenopausal women is a highly predictive marker for response to antiestrogen treatment. Tamoxifen, an antiestrogen, that competitively blocks the actions of 17β-estradiol (E 2 ), binds and activates ER-? in breast tumors and is used for treating all stages of breast cancer. Although tamoxifen is effective in reducing recurrence fromER-positive early stage breast cancer, approximately 50% of patients do not benefit from its use, because their breast cancers have intrinsic or de novo tamoxifen-resistance. Additionally, most patients that do initially benefit from tamoxifen, will develop acquired resistance to the drug during the treatment regimen. Despite increasing use of the aromatase inhibitors as breast cancer therapies, tamoxifen remains the hormonal therapy of choice in premenopausal women, and is the only hormonal therapy approved for breast cancer prevention. Therefore, a current goal in breast cancer research is to elucidate the mechanisms of both intrinsic and acquired resistance to tamoxifen and other antiestrogens in order to develop new therapeutic strategies to prevent and/or treat resistant breast cancer.