Chemical Probes of Rapid Estrogen Signaling in Breast Cancer Treatment and Chemoprevention

Estrogens and antiestrogens are important in the development, treatment and possible chemoprevention of breast cancer. Rapid estrogen responses happen too quickly to involve transcription and there is much debate as to the mechanisms by which they operate and their relevance to breast cancer. This proposal aims to design and use selective chemical probes to answer those questions. Progress has been made in the synthesis of a screening panel to probe the role of rapid estrogen responses in breast cancer proliferation and resistance chemotherapy. We have generated new, potent compounds based on tamoxifen and estradiol core structures including endoxifen, a compound since discovered to be a major bioactive metabolite of tamoxifen and possibly a predictor of successful tamoxifen response in patients. We have shown for the first time that a number of SERMs like tamoxifen and raloxifene can activate ERK phosphorylation identically to estradiol. We have also generated the first tamoxifen-polymer conjugate that is capable to binding to estrogen receptor in vitro as well as activate rapid responses in breast cancer cell lines. Ongoing studies will use these compounds to better understand rapid estrogen signaling and make better therapeutic and chemopreventive agents for breast cancer.