(Applicants' Abstract)): This is a 5-year application by a new investigator, submitted in response to PA-99-162 (Stages of breast development: normal to metastatic disease). The critical contribution of estrogen receptor (ER) in breast cancer development indicates that any changes in ER regulation could contribute to breast tumor development. The identification and characterization of nuclear receptor coactivators adds further complexity to the regulatory mechanisms involving the transcriptional activity of nuclear receptors. We are particularly interested in two nuclear receptor coactivators, PBP (Peroxisome proliferator receptor Binding Protein) and PRIP (Peroxisome proliferator Receptor Interacting Protein), which we identified and characterized as two novel coactivators. Our recent studies showed that PBP and PRIP genes serve as coactivators for ER and are amplified and overexpressed in breast cancer . We hypothesize that PBP and PRIP exert a critical role in mammary epithelial growth and participate in the development of human breast cancer by perturbing normal ER signaling. The long term goal of this study is to understand the mechanism of transcriptional regulation by nuclear receptor coactivators and how the interruption of this regulation contributes to tumorigenesis.
Three Specific Aims are proposed: (1) To test the hypothesis that PBP and PRIP overexpression promote breast tumorigenesis by increasing ER activity; (2) To generate mouse models with disrupted PBP and PRIP gene to delineate their in vivo function in mammary gland development and differentiation; (3) To investigate how PRIP acts as a coactivator by characterizing PIPMT (PRIP Interacting Protein with MethylTransferase domain), cloned by us, and by isolating and characterizing other PRIP associated proteins. These studies will provide new information on the function of nuclear receptor coactivators during normal and neoplastic breast development.
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