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Chemical Probes of Rapid Estrogen Signaling in Breast Cancer Treatment and Chemoprevention
Annual rept. 1 Apr 2005-31 Mar 2006
PURDUE UNIV LAFAYETTE IN
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Estrogens and antiestrogens are important in the development, treatment and possible chemoprevention of breast cancer. Many reports have suggested that there are a number of signaling responses to estrogens and antiestrogens that are independent of the classic transcriptional model of estrogen receptor action, but there is much controversy as to the mechanisms underlying these responses and their overall relevance to breast cancer. This proposal aims to design and use selective chemical probes to answer those questions. A screening panel has been synthesized to probe the role of these estrogen responses in breast cancer proliferation and resistance chemotherapy. We have learned more about the structure activity relationships necessary for potent ER modulators. We have discovered new responses via serum response factor that appear to be downstream of rapid estrogen signaling. We have discovered that tamoxifen-polymer conjugates are efficiently taken up by breast cancer cells in a specific manner and possess highly potent biological activity. We have also generated the first tamoxifen-conjugated nanoparticles and have demonstrated their biological activity. Ongoing studies will use these compounds and constructs to better understand estrogen signaling and make better therapeutic and chemopreventive agents for breast cancer.
APPROVED FOR PUBLIC RELEASE