ANDROGEN RECEPTOR FUNCTION IN PROSTATE CANCER

前列腺癌是美国癌症死亡的第二大原因 男人患者死于雄激素非依赖性转移性疾病。 雄激素通过激活前列腺上皮细胞来调节前列腺癌的生长。 雄激素受体雄激素非依赖性前列腺癌被认为 从缺乏雄激素受体的前列腺癌细胞发展而来。但是，在这方面， 雄激素非依赖性前列腺癌表达雄激素受体水平 与良性前列腺组织和雄激素中的蛋白质相似， 依赖性前列腺癌雄激素非依赖性生长可能是由于 雄激素受体突变改变特异性或类固醇结合， 对肾上腺雄激素敏感。报告的突变频率 差异很大，只有6个突变进行了功能分析。我们 将检验雄激素受体功能改变是一种 前列腺癌的治疗方法有哪些？在目标1中，分子 雄激素受体基因的改变将在 雄激素依赖性癌症是器官局限性的，局部侵袭性的，或 局部复发的转移性和雄激素非依赖性癌症，或 转移性的同样数量的白人和非洲裔美国人将被 研究了变性梯度凝胶电泳法和单克隆抗体法 链构象多态性将用于筛选点 雄激素受体的突变谷氨酰胺和甘氨酸重复 将分析外显子A中的区域，因为多态性或缺失可能 增强雄激素受体mRNA或蛋白质表达。将使用RT-PCR 寻找异常剪接，如在雌激素中观察到的， 孕激素受体在乳腺癌中的作用， 前列腺癌在目标2中，类固醇结合和瞬时共转染 将使用测定来确定突变体的功能特征。 雄激素受体在目标3，表达和亚细胞定位 野生型和突变型雄激素受体在雄激素依赖性和 独立的前列腺癌将使用免疫组织化学进行评价 和图像分析。前列腺癌系列活检结果分析 通过去势治疗的患者将允许雄激素的时间比较， 受体蛋白表达与细胞增殖的关系。的作用 雄激素受体基因扩增在雄激素发育中的作用 独立性将使用南方分析和现场 杂交方法获得的洞察力应该可以更全面地了解 雄激素受体在雄激素转化过程中的作用 依赖性前列腺癌和非依赖性前列腺癌

Prostate cancer is the second leading cause of cancer death in American men. Patients succumb to androgen-independent metastatic disease. Androgens regulate the growth of prostate cancer through activation of the androgen receptor. Androgen-independent prostate cancer was thought to develop from prostate cancer cells lacking androgen receptors. However, androgen-independent prostate cancer expresses levels of androgen receptor proteins similar to those seen in benign prostate tissue and androgen- dependent prostate cancer. Androgen-independent growth could result from androgen receptor mutations that alter specificity or steroid binding or sensitivity to adrenal androgens. The frequency of mutations reported varies widely and only 6 mutations have been functionally analyzed. We will test the hypothesis that altered androgen receptor function is a critical event in the progression of prostate cancer. In Aim 1, molecular alterations in the androgen receptor gene will be searched for in androgen-dependent cancers that are organ-confined, locally invasive or metastatic and androgen-independent cancers that are locally recurrent or metastatic. An equal number of Caucasians and African Americans will be studied. The methods of denaturing gradient gel electrophoresis and single strand conformation polymorphism will be used to screen for point mutations in the androgen receptor. The glutamine and glycine repeat regions in exon A will be analyzed since polymorphisms or deletions may enhance androgen receptor mRNA or protein expression. RT-PCR will be used to search for abnormal splicing such as has been observed in estrogen and progesterone receptors in breast cancer but has not been reported in prostate cancer. In Aim 2, steroid binding and transient co-transfection assays will be used to determine the functional characteristics of mutant androgen receptors. In Aim 3, the expression and subcellular localization of wild-type and mutant androgen receptors in androgen-dependent and independent prostate cancer will be evaluated using immunohistochemistry and image analysis. Analysis of serial biopsies of prostate cancer from patients treated by castration will allow temporal comparison of androgen receptor protein expression with cellular proliferation. The role of androgen receptor gene amplification in the development of androgen independence will be determined using southern analysis and in situ hybridization. Insights gained should allow a more complete understanding of the role of the androgen receptor in the transition from androgen- dependent to independent prostate-cancer.