Androgen receptor signaling and mutations in prostate cancer.
Androgen receptor signaling and mutations in prostate cancer.
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DOI：
10.1038/aja.2010.89
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发表时间：
2010-09
影响因子：
2.9
通讯作者：
Koochekpour, Shahriar
中科院分区：
文献类型：
--
作者：
Koochekpour, Shahriar
前列腺的正常和肿瘤生长依赖于雄激素受体（AR）的表达和功能。AR的雄激素激活及其共调节因子是导致AR靶基因转录活性的经典途径。或者，生长因子、神经营养肽、细胞因子或非雄激素激素对AR的细胞质信号传导串扰可能在前列腺癌发生和疾病的转移性或雄激素非依赖性（AI）进展中具有重要作用。此外，各种核转录因子通过基础转录机制作用的交叉调节可以积极或消极地影响AR或AR靶基因的表达和活性。雄激素消融导致大量患者的初始有利反应;然而，几乎无一例外地患者复发，具有称为去势抵抗性或去势难治性前列腺癌（PCa）的疾病的侵袭性形式。了解导致PCa细胞抵抗雄激素剥夺治疗的关键分子事件对于开发成功的治疗难治性疾病至关重要。在相当数量的难治性患者中，AR过表达、突变或基因组扩增。这些遗传改变保持了高度敏感的AR的活性存在，该AR对雄激素、抗雄激素或非雄激素激素有反应，并共同赋予PCa细胞选择性生长优势。本文综述了AR结构、AR辅助调节因子、AR的翻译后修饰、前列腺上皮细胞和基质细胞中AR功能的双重性、AR依赖性信号传导、体细胞和生殖细胞突变形式的遗传变化及其在前列腺癌细胞和组织中已知的功能意义。
Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.
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影响因子：
6
作者：
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通讯作者：
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