Development of Androgen Independent Prostate Cancer

描述(申请人提供)：雄激素受体(AR)和反式激活AR的因子似乎对前列腺癌的发展和进展有最大的影响。通过联合雄激素阻断去除雄激素并不一定意味着AR信号通路是沉默的，因此不参与雄激素非依赖性疾病的进展。我们已经建立了一种原代的人前列腺上皮细胞转染实验，可以直接测量这些细胞从雄激素依赖到雄激素非依赖生长过程中雄激素受体(AR)的生物活性。本研究的假设是，雄激素非依赖性前列腺癌的发生要么是通过AR/辅助调节因子的相互作用，要么是通过其他因素的相互作用，这些因素可以直接结合到相同的AR DNA结合位点。这项研究的具体目的是： I.表征原代HPE细胞中AR的生物学活性，代表向雄激素非依赖性的进展。 II.从与AR或ARBS-2直接结合的原代HPE细胞中分离共调节因子。 Iii.确定已确定的协同调节器与AR或ARBS-2的合作相互作用。 我们的长期目标是阐明转向雄激素非依赖性前列腺癌的机制。AR反式激活促进雄激素非依赖性前列腺癌发生的分子机制可以转化为临床上有价值的工具，作为预后的标志物，为预测激素对雄激素剥夺的反应提供一种分析方法，并为新的治疗提供潜在的靶点。

DESCRIPTION (provided by applicant): 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.