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生长。尽管AR激活的靶点仍不清楚，但它们被认为对细胞增殖至关重要，因为大多数前列腺癌表达AR并且是雄激素依赖性的。1941年，Charles Huggins和Clarence Hodges证明了雄激素的消耗导致前列腺肿瘤的显著消退，并预示着现在普遍存在的雄激素剥夺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，患上更具侵袭性的前列腺癌，称为去势抵抗性前列腺癌（CRPC）。CRPC没有有效的治疗选择，这是导致该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AR基因扩增。全球基因表达谱显示AR是CRPC中唯一持续上调的基因，表明AR在疾病进展中具有重要意义。我们和其他人已经提供了多条证据，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依赖性”的，并且AR可以用作可能的治疗靶标。然而，AR在前列腺癌进展和CRPC发展中的确切作用仍不清楚。进展有限的主要原因之一是缺乏可用于评估疾病进展过程中配体非依赖性AR作用的适当动物模型。为了解决这个问题，我们开发了几种新型小鼠模型，使我们能够研究雄激素非依赖性但AR依赖性的前列腺癌的进展，模拟大多数人前列腺癌中通常发生的情况。在这一竞争性更新中，我们提出了三个不同但综合的具体目标，以直接测试我们的中心假设，即AR的异常激活失调细胞分化和增殖，直接导致前列腺癌的发生和进展。在本申请中提出了三个具体的目的，以解决三个不同但相关的问题：1）AR的异常激活如何促进肿瘤进展？2)AR的异常激活是否诱导ETS蛋白的表达和激活促进前列腺癌的进展？3)前列腺癌进展和CRPC发展中AR异常激活的分子机制是什么？

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?