ANDROGEN RECEPTOR GENE STRUCTURE AND FUNCTION IN HUMAN PROSTATE CANCER

人类前列腺癌中的雄激素受体基因结构和功能

• 批准号: 6203262
• 负责人: EVELYN R BARRACK
• 金额: $ 16.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-04 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203262
• 关键词: African American; androgen receptor; gene mutation; hormone related neoplasm /cancer; human genetic material tag; human tissue; molecular oncology; neoplasm /cancer genetics; polymerase chain reaction; prostate neoplasms; protein structure function; tissue /cell culture; transfection

The highest risk factor for prostate cancer is androgen action. Men castrated before puberty do not develop prostate cancer and the experimental induction of prostate carcinogenesis in animals requires androgen. Androgen could play a role in the process of carcinogenesis, progression to clinically manifest disease, progression from nonaggressive to aggressive disease, or simply the growth of prostate tumor cells. The androgen receptor (AR) could even play a role in androgen-independent tumors that continue to express AR if the AR could be activated in the absence of androgen. Our long term goal is to understand the role(s) of the AR in prostate cancer, and to determine whether this role is mediated by a normal AR or by abnormal AR. Our discovery of AR aggressive tumors. Aim 1 is to expand our studies to specific subpopulations, and, in addition, determine whether tumors that lack gene mutations in the AR coding sequence nevertheless produce AR variants. We will screen for AR mutations in early stage tumors that had already progressed prior to radical prostatectomy, despite a lack of evidence of metastic spread, and in high grade/low volume tumors that may represent a more aggressive form of prostate cancer, having acquired a more ominous phenotype early in its course. In addition, we will determine whether AR mutations occur in prostate cancers from African-Americans; the higher incidence and mortality of prostate cancer in African-Americans than in Caucasians may be due to more aggressive disease. We will also determine whether prostate cancer produces AR mRNA splice variants that lack one or more exons, and truncated AR protein variants that arise from translation initiation at a downstream methionine. Tumors with such variants could manifest altered AR function despite a wild- type AR gene. If AR variants are found in prostate cancer, we will determine whether they also exist in normal prostate tissue. Aim 2 is to characterize the properties of normal AR and abnormal AR variants found in prostate cancer. We will determine whether mutations found in early stage and late stage disease affect AR function in the same way, and whether even normal AR may exhibit altered activity under certain conditions. We will determine whether normal AR or AR variants can be activated by nonandrogenic steroids, antiandrogens, or activators of intracellular protein phosphorylation signaling pathways. Variants will include those that result from AR gene mutation, alternative mRNA splicing, and alternative translation initiation site utilization. We will determine whether glutamine and/or glycine repeat length modulates the properties of these variants. Variant AR expression vectors will be constructed and transfected into AR negative cells (e.g., prostate cancer cells, immortalized normal prostate epithelial cells). Transcriptional activity will be monitored by co- transfecting an androgen responsive reporter gene.

前列腺癌的最高危险因素是雄激素的作用。 青春期前阉割的男性不会患前列腺癌 动物前列腺癌的实验诱导 需要雄激素。 雄激素可能在这个过程中发挥作用 癌发生、进展为临床表现的疾病、 从非侵袭性疾病进展为侵袭性疾病，或者简单地说 前列腺肿瘤细胞的生长。 雄激素受体（AR）可以 甚至在不依赖雄激素的肿瘤中发挥作用，这些肿瘤继续 如果 AR 可以在没有雄激素的情况下被激活，则表达 AR。 我们的长期目标是了解 AR 在 前列腺癌，并确定这种作用是否由 正常 AR 或异常 AR。 我们发现 AR 具有侵略性 肿瘤。 目标 1 是将我们的研究扩展到特定的亚人群， 此外，确定肿瘤是否缺乏基因突变 然而，AR 编码序列中仍然会产生 AR 变体。 我们 将在已经发生的早期肿瘤中筛查 AR 突变 尽管缺乏 转移扩散的证据，以及高级别/低体积肿瘤 这可能代表一种更具侵袭性的前列腺癌， 在其病程早期就获得了更不祥的表型。 在 另外，我们将确定前列腺中是否发生AR突变 来自非裔美国人的癌症；发病率和死亡率较高 非裔美国人前列腺癌的发病率可能高于白种人 由于更具侵袭性的疾病。 我们还将确定是否 前列腺癌产生缺乏一种或多种的 AR mRNA 剪接变体 更多的外显子和截短的 AR 蛋白变体 翻译起始于下游蛋氨酸。 肿瘤与 尽管存在野生的，但此类变体可能会表现出改变的 AR 功能 AR型基因。 如果在前列腺癌中发现 AR 变异，我们将 确定它们是否也存在于正常前列腺组织中。 目的 2是表征正常AR和异常AR的特性 在前列腺癌中发现的变异。 我们将确定是否 早期和晚期疾病中发现的突变影响 AR 以同样的方式发挥作用，甚至普通的 AR 是否也会表现出 在某些条件下改变活性。 我们将确定 正常的 AR 或 AR 变体是否可以被非雄激素激活 类固醇、抗雄激素或细胞内蛋白激活剂 磷酸化信号通路。 变体将包括那些 AR 基因突变、mRNA 选择性剪接导致的 替代翻译起始位点的利用。 我们将 确定谷氨酰胺和/或甘氨酸重复长度是否调节 这些变体的属性。 变体 AR 表达载体 将构建并转染至 AR 阴性细胞（例如， 前列腺癌细胞，永生化正常前列腺上皮细胞 细胞）。 转录活动将由共同监测 转染雄激素反应报告基因。