Androgen signaling through androgen receptor (AR) plays a pivotal role in control of cell proliferation and differentiation in the development and progression of prostate cancer. AR, a hormone regulated transcription factor, regulates dynamic gene expression programs. However, how the function of AR is altered from its pro-differentiation in normal prostate epithelium to pro-proliferation and tumor growth in prostate cancer is poorly understood. Through functional genomics, we have uncovered a novel nuclear ATPase coregulator protein that physically and functionally associates with AR and other key cell signaling regulators. Strikingly, this coregulator is induced by androgen in androgendependent cancer cells, highly expressed and possibly amplified in androgen-independent cells and tumors. Our preliminary studies also reveal that it plays very unique functions by specifically mediating the pro-proliferation and survival signaling pathways in prostate cancer cells and, at the same time, suppressing the androgen-induced differentiation program. Taking together, we hypothesize that this coregulator is a key mediator of specific AR function in AR's tumorigenic signaling through its dualistic switch mechanism and that its aberrant function represents an important mechanism of the conversion of prostate cancer to the hormone-refractory state. To test our hypothesis, we propose to establish its role in prostate cancer cell cycle progression, cell survival and invasion and define the specific signaling pathways integrated by this AR coregulator. To examine its function in a physiologically relevant setting, we will determine how its aberrant function affects tumor growth and progression to hormone deprivation therapy resistant status. The completion of the proposed study will provide new insights into the molecular underpinnings of AR-mediated tumorigenic signaling in prostate cancer and lead to a novel therapeutic strategy in treatment of the disease.
This proposed study will examine how a newly found, nuclear switch protein works together with the key male hormone receptor i.e. the androgen receptor or AR to selectively mediate the receptor's pro-tumorigenic function during prostate cancer progression from androgen-dependent to the androgen hormone deprivation-resistant status. Understanding the process will provide novel insights to the underlying molecular mechanisms of prostate cancer progression, which will be valuable to the design of new treatment regimens. As the novel protein has an enzymatic activity and its level is possibly elevated in prostate cancers, studying how it functions will also provide molecular basis for targeting this new protein.
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