Breast cancer is among the most devastating diseases affecting women. The risk for a North American women getting breast cancer has doubled since 1940, and at present one woman in eight is at risk of developing the disease. Estrogens play a significant role in the development of breast cancer. The mitogenic action of estrogen is amplified by the hormone-dependent transcription factor, estrogen receptor (ER), which assembles transcription accessory proteins in a ligand dependent manner. This multifaceted process is largely aided by the ligand-induced conformational adjustments in the ligandbinding domain (LBD) of ER. However, the contribution of the neighboring F-domain in this critical stage of ER action is not well understood. We hypothesize that the F-domain of ERa contributes to the ligandinduced conformation of the LBD, which determines the recruitment of comodulators onto ER for its function.
In Aim 1, we will focus on the role of ERa F-domain in the ligand-dependent recruitment of coactivators. We have designed several approaches to address this issue, which include coactivator recruitment by F-domain mutants in the absence and presence of chromatin.
Aim 2 will measure the consequence of F-domain perturbation on the biological properties of ERa.
In Aim 3, we will employ NMR analysis to address the most pressing question of whether F-domain affects the overall topology of the LBD. In the absence of a crystal structure of the E-F domain, our results from this Aim will, for the first time, shed light on E-F domain's solution structure. This will greatly aid us in understanding the mechanism of ERa actions.
Aim 4 will determine if the F-domain influences the non-genotropic actions of ER. We expect that a successful completion of our objectives will not only provide a greater understanding of estrogen receptor actions, but will also provide new opportunities to develop novel pharmacological compounds to antagonize the mitogenic actions of estrogens.
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