Androgen Signaling in prostate cancer progression and CRPC development

描述(申请人提供)：雄激素受体(AR)是一种核激素受体，通过激活其下游靶基因促进前列腺癌的生长。尽管AR激活的靶点尚不清楚，但它们被认为对细胞增殖至关重要，因为大多数前列腺癌都表达AR，并依赖于雄激素。1941年，查尔斯·哈金斯和克拉伦斯·霍奇斯证明，雄激素的枯竭会导致前列腺癌的显著消退，并预示着现在普遍存在的雄激素剥夺疗法治疗前列腺癌的策略。不幸的是，在开始治疗后的两到三年内，大多数患者总是复发，出现一种更具侵袭性的前列腺癌，称为去势抵抗前列腺癌(CRPC)。CRPC没有有效的治疗选择，这是导致这种疾病死亡的主要原因。在雄激素消融治疗后，几乎三分之一的前列腺癌中观察到了AR基因的扩增。全球基因表达谱显示，AR是CRPC中唯一持续上调的基因，暗示AR在疾病进展中的重要性。我们和其他人已经提供了多种证据证明AR在配体非依赖性细胞生长中的关键作用，这意味着雄激素非依赖性细胞可能仍然是“AR依赖的”，AR可以被用作可能的治疗靶点。然而，AR在前列腺癌进展和CRPC发生中的确切作用仍不清楚。进展有限的主要原因之一是缺乏合适的动物模型来评估疾病进展过程中配体非依赖性AR的作用。为了解决这个问题，我们开发了几个新的小鼠模型，使我们能够研究前列腺癌的进展，这种前列腺癌不依赖雄激素，但依赖AR，模拟大多数人类前列腺癌通常发生的情况。在这一相互竞争的更新中，我们提出了三个不同但综合的特定目标来直接测试我们的中心假设，即AR的异常激活导致细胞分化和增殖失调，而细胞分化和增殖直接导致前列腺癌的发生和发展。本研究针对三个不同但相关的问题提出了三个具体的目标：1)AR异常激活如何促进肿瘤进展？2)AR异常激活是否诱导Ets蛋白表达和激活促进前列腺癌进展？3)AR异常激活在前列腺癌进展和CRPC发生中的分子机制是什么？

DESCRIPTION (provided by applicant): The androgen receptor (AR) is a nuclear hormone receptor and promotes prostate cancer growth through activation of its downstream target genes. Although the targets of AR activation remain unclear, they are believed to be critical for cellular proliferation because most prostate cancers express the AR and are androgen-dependent. That depletion of androgens results in significant regression of prostate tumors was demonstrated in 1941 by Charles Huggins and Clarence Hodges and heralded what is now the ubiquitous strategy of androgen deprivation therapy to treat prostate cancer. Unfortunately, within two to three years after initiating therapy, most patients invariably relapse with a more aggressive form of prostate cancer, known as castration resistant prostate cancer (CRPC). There is no effective treatment option for CRPC, which has mainly contributed to the mortality of the disease. AR gene amplification has been observed in almost one-third of prostate cancers after androgen ablation therapy. Global gene expression profiling shows AR as the only gene to be consistently up-regulated in CRPC, implicating the significance of AR in disease progression. We and others have provided multiple lines of evidence demonstrating a critical role of AR in ligand-independent cell growth, implying that androgen- independent cells may still be "AR dependent" and that the AR can be used as a possible therapeutic target. However, the precise role of the AR in prostate cancer progression and CRPC development is still unclear. One of the main reasons for the limited progress is the lack of appropriate animal models that can be used to evaluate ligand independent AR action during the course of disease progression. To address this, we have developed several novel mouse models that allow us to investigate the progression of prostate cancer that is androgen independent but AR-dependent, mimicking what typically occurs in most human prostate cancers. In this competing renewal, we propose three different but integrated specific aims to directly test our central hypothesis that abnormal activation of AR dysregulates cell differentiation and proliferation that directly contribute to prostate cancer initiation and progression. Three specific aims are proposed in this application to address three different but related questions: 1) how abnormal activation of AR promotes tumor progression? 2) does aberrant activation of AR induce expression and activation of ETS proteins in promoting prostate cancer progression? 3) what are the molecular mechanisms underlying aberrant activation of AR in prostate cancer progression and CRPC development?