Cancer Therapy: Preclinical Bazedoxifene Exhibits Antiestrogenic Activity in Animal Models of Tamoxifen-Resistant Breast Cancer: Implications for Treatment of Advanced Disease

Purpose: There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-a) antagonists, or that downregulate the expression of ER-a, would have clinical use in the treatment of advanced tamoxifenand aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-a pharmacology, that theremay already exist among themost recently developed selective estrogen receptormodulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. Experimental Design: A validatedmolecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-a conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. Results:Thehigh-affinity SERMbazedoxifenewas shown to function as a pure ER-a antagonist in cellular models of breast cancer and effectively inhibited the growthof both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-a that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist