The androgen receptor (AR) and the factors that transactivate the AR appear to have the greatest impact on the development and progression of prostate cancer. The removal of androgen by combined androgen blockade does not necessarily mean that the AR signaling pathway is silent and therefore not involved in the progression to androgen-independent disease. We have developed a primary, human prostate epithelial cell transfection assay that can measure the biological activity of the androgen receptor (AR) directly in these cells during the progression from androgen-dependent to androgen-independent growth. The HYPOTHESIS of this study is that the development of androgen-independent prostate cancer is modulated either through AR/co-regulator interactions or through the interactions of other factors which can bind directly to the same AR DNA binding site.
The SPECIFIC AIMS of this study are: I. Characterizing the biological activity of the AR in primary HPE cells which represent the progression to androgen-independence. II. Isolating co-regulators from primary HPE cells that bind to AR or to ARBS-2 directly. III. Defining the cooperative interaction of the identified co-regulators with AR or ARBS-2. Our long term goals are to elucidate the mechanisms that govern the switch to androgen-independent human prostate cancer. The molecular mechanisms by which transactivation of the AR facilitates the development of androgen-independence prostate cancer could translate into valuable tools in the clinic as markers for prognosis, provide an assay for predicting hormonal responsiveness to androgen deprivation, and provide potential targets for novel therapies.
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