Androgen Signaling in prostate cancer progression and CRPC development

描述（由申请人提供）：雄激素受体（AR）是一种核激素受体，通过激活其下游靶基因来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表达AR并且依赖雄激素。1941年，查尔斯·哈金斯和克拉伦斯·霍奇斯证明了雄激素的消耗会导致前列腺肿瘤的显著消退，并预示着现在雄激素剥夺疗法治疗前列腺癌的普遍策略。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为一种更具侵袭性的前列腺癌，即去势抵抗性前列腺癌（CRPC）。CRPC没有有效的治疗选择，这是导致该病死亡的主要原因。近三分之一的前列腺癌患者在雄激素消融治疗后出现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，提示AR在疾病进展中的重要意义。我们和其他人提供了多种证据，证明AR在不依赖配体的细胞生长中起关键作用，这意味着不依赖雄激素的细胞可能仍然是“AR依赖”的，并且AR可以用作可能的治疗靶点。然而，AR在前列腺癌进展和CRPC发展中的确切作用尚不清楚。进展有限的主要原因之一是缺乏合适的动物模型，可用于评估疾病进展过程中与配体无关的AR作用。为了解决这个问题，我们开发了几种新的小鼠模型，使我们能够研究雄激素独立但ar依赖的前列腺癌的进展，模拟大多数人类前列腺癌的典型情况。在这个相互竞争的更新中，我们提出了三个不同但综合的特定目标来直接验证我们的中心假设，即AR的异常激活失调了细胞分化和增殖，直接促进了前列腺癌的发生和发展。在本应用中提出了三个具体目标，以解决三个不同但相关的问题：1)AR异常激活如何促进肿瘤进展？2)异常激活AR是否诱导ETS蛋白的表达和激活，从而促进前列腺癌的进展？3)前列腺癌进展和CRPC发生过程中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?