ANDROGEN RECEPTOR EXPRESSION AND FUNCTION IN PROSTATE CANCER

雄激素在癌症的发生和发展中起着重要作用。雄激素通过激活雄激素受体发挥作用。虽然大多数患者在雄激素剥夺治疗后雄激素受体表达缺失，但雄激素非依赖性前列腺癌的雄激素受体蛋白表达水平与雄激素依赖型前列腺癌和良性增生症相似。这一观察结果表明，雄激素受体在雄激素非依赖性前列腺癌的生长调节中可能与雄激素依赖型前列腺癌和良性增生一样重要。由于前列腺癌在非裔美国人中比白人更频繁和更具侵袭性，如果雄激素受体对前列腺癌的增殖调控至关重要，那么雄激素受体在非裔美国人中的重要性应该比在白人前列腺组织中更明显。然而，对雄激素受体的研究几乎没有包括非裔美国人的组织。我们将检验这一假设，即雄激素受体的表达和功能的变化对进展至关重要。这些变化在高加索人和非裔美国人之间可能不同。在目标1中，我们将使用自动视频图像分析来比较雄激素受体的表达和雄激素受体潜在激活物的组织水平，在高加索人和美国人中雄激素依赖和雄激素非依赖性前列腺癌。在目标2中，我们将在相同的研究样本中寻找雄激素受体基因的分子变化，并确定这些变化是否影响雄激素受体的表达。将使用变性梯度凝胶电泳法和单链构象多态技术筛选雄激素受体的点突变。瞬时共转染试验将确定突变雄激素受体的功能特征。外显子A的谷氨酰胺和甘氨酸重复区域的长度将通过直接测序来确定。在目标3中，对去势治疗的前列腺癌患者的一系列活检组织的分析将允许在时间上比较雄激素受体蛋白的表达，从增殖开始时雄激素受体和细胞增殖组织的分子变化将被用来分别在项目2和项目3中探索雄激素依赖的人前列腺癌CWR22异种移植瘤和再生大鼠前列腺中雄激素受体激活和雄激素调节基因表达的潜在机制。所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非依赖性前列腺癌发展中的作用。

Androgens play an important role in cancer development and progression. Androgens exert their effects through activation of the androgen receptor. Although androgen receptor expression is lost following androgen deprivation therapy that induces clinical remission in most patients, androgen-independent prostate cancers express levels of androgen- receptor protein similar to those found in androgen-dependent prostate cancer and benign hyperplasia. This observation suggests that the androgen receptor may be as important for growth regulation in androgen-independent prostate cancer as it is in androgen-dependent prostate cancer and benign hyperplasia. Since prostate cancer develops more frequently and is more aggressive in African Americans than in Caucasians and, if the androgen receptor is critical for the regulation of proliferation of prostate cancer,, the importance of the androgen receptor should be even more apparent in African American than in Caucasian prostatic tissues. Yet, few if any, studies of the androgen receptor include tissues from African Americans. We will test the hypothesis that changes in the expression and function of the androgen receptor are critical to the progression. of prostate cancer and that these changes may differ between Caucasian and African Americans. In Aim 1, we will use automated video image analysis to compare androgen receptor expression and tissue levels of potential activators of the androgen receptor in androgen dependent versus androgen-independent prostate cancer in Caucasian versus American Americans. In Aim 2, we will search for molecular alterations in the androgen receptor gene in these same research specimens and determine whether these changes affected androgen receptor expression. Point mutations in the androgen receptor will be screened for using denaturing gradient gel electrophoresis and single stranded conformational polymorphism. Transient co-transfection assays will determine the functional characteristics of the mutant androgen receptors. The lengths of the glutamine and glycine repeat regions of exon A will be determined by direct sequencing. In Aim 3, analysis of serial biopsies of prostate cancer from patients treated by castration will allow temporal comparison of androgen receptor protein expression, molecular changes in the androgen receptor and cellular proliferation Tissue from the time of onset of proliferation will be used to explore potential mechanisms of androgen receptor activation and expression of androgen-regulated genes developed in the androgen-dependent CWR22 human prostate cancer xenograft and the regenerating rat prostate in Projects 2 and 3, respectively.. Insights gained should allow a more complete understanding of the role of the androgen receptor in the development of androgen-independent prostate cancer.