MECHANISM OF ESTROGEN RECEPTOR DOWN REGULATION

University Of Wisconsin Madison, Madison WI

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Abstract

DESCRIPTION: (Applicant's Description) Estrogen mediates its actions on reproductive tissues, such as the breast and uterus, by binding to the estrogen receptor (ER), a nuclear, ligand-dependent transcription factor. The ER content, therefore, is a crucial determinant in the cell's ability to respond to estrogen as exemplified by the use of ER status in the prognosis for endocrine therapy in breast cancer patients. The applicant's long term research goal is to investigate the mechanisms governing ER protein expression and function. To this end, she has initiated studies into the regulation of ER by estrogen and identified a novel proteolytic mechanism involved in autologous down-regulation of the ER in pituitary and breast cancer models. The objectives of this project are to: 1) Determine the functional consequence of extending the ER half-life. These studies examine alterations in ER transactivation and estrogen-binding functions under conditions in which ER does not degrade in response to estrogen. 2) Identify the parameters controlling ER degradation. Mutational analysis will be performed on the ER with emphasis on phosphorylation, DNA binding, and nuclear localization sites to map the coding sequences required for the estrogen-induced degradation response. The results of these studies will represent the foundation for future investigations into the regulatory mechanisms coupling estrogen receptor status to function. This analysis takes advantage of her expertise in reproductive endocrinology and expands her training in steroid receptor biochemistry and tumor biology. In the Department of Physiology at the University of Wisconsin-Madison, she has the opportunity to develop this research into an independent program in a supportive environment that is committed to her success as a principal investigator in academia. The attainment of a faculty position within this department will be a critical step toward her goal to contribute to the scientific community as both a researcher and a mentor.