The Role of beta-adrenergic Signaling in Prostate Cancer

描述（由申请人提供）：前列腺癌（PCa）是美国男性癌症相关死亡的主要原因。像其他癌症一样，PCa在内在线索和外在因素的背景下发展。不同的基因和蛋白质组决定了从前列腺前驱病变到局部PCa，最后到转移性疾病的进展。临床局部PCa可以使用手术或放射治疗有效消融。然而，激素难治性转移性疾病总是无法治愈并导致死亡。因此，表征调节转移性PCa生长的基因与前列腺癌研究特别相关，并且可以提供治疗干预的新靶点。我们确定的这些基因之一是EZH 2，这是一种在侵袭性癌症中上调的Polycomb组蛋白。EZH 2的失调通过抑制一组关键的肿瘤抑制基因（包括ADRB 2，β-肾上腺素能信号通路的关键调节因子）促进肿瘤进展。ADRB 2是EZH 2介导的转录抑制的直接靶点，并可作为PCa的预后生物标志物。然而，ADRB 2在PCa中的功能及其下游细胞信号级联仍不清楚。我的长期目标是了解调节癌症进展的分子机制。本申请的目的是表征ADRB 2在PCa中的作用。我们的中心假设是ADRB 2的表达失调通过破坏细胞信号传导途径促进前列腺癌的进展。本提案的具体目的如下：具体目的1：确定ADRB 2在前列腺癌中的表达模式和临床相关性。具体目标2：表征ADRB 2在调节前列腺癌生长和发展中的作用。具体目标3：了解ADRB 2作为前列腺癌肿瘤抑制因子的机制。总之，本提案涉及ADRB 2在前列腺癌生长和发展中的表达、功能作用和潜在机制。我们最终的希望是，ADRB 2在转移性前列腺癌中的功能特征有朝一日将导致这种致命疾病的有效治疗。

DESCRIPTION (provided by applicant): Prostate Cancer (PCa) is a leading cause of cancer-related death in American men. Like other cancers, PCa develops in the background of intrinsic cues and extrinsic factors. Distinct sets of genes and proteins dictate progression from precursor lesion of the prostate, to localized PCa, and finally to metastatic disease. Clinically localized PCa can be effectively ablated using surgical or radiation treatments. Hormone-refractory metastatic disease, however, is invariably incurable and leads to death. Therefore, characterizing the genes that regulate the growth of metastatic PCa are of particular relevance to prostate cancer research and may offer novel targets for therapeutic intervention. One of these genes we identified was EZH2, a Polycomb group protein that is up-regulated in aggressive cancers. Dysregulation of EZH2 promotes tumor progression through the repression of a key set of tumor suppressor genes, including ADRB2, a critical regulator of the beta-adrenergic signaling pathway. ADRB2 is a direct target of EZH2-mediated transcriptional repression and may serve as a prognostic biomarker in PCa. However, ADRB2 function and its downstream cellular signaling cascade in PCa remain unclear. My long-term goal is to understand the molecular machineries regulating cancer progression. The objective of this application is to characterize the role of ADRB2 in PCa. Our central hypothesis is that dysregulated expression of ADRB2 promotes prostate cancer progression through disrupted cellular signaling pathways, The specific aims of this proposal will be as follows: Specific Aim 1: Determine expression pattern and clinical correlation of ADRB2 in prostate cancer. Specific Aim 2: Characterize the role of ADRB2 in regulating prostate cancer growth and development. Specific Aim 3: Understand the mechanism of ADRB2 as a tumor suppressor in prostate cancer. In summary, this proposal addresses the expression, functional roles, and underlying mechanisms of ADRB2 in the growth and development of prostate cancer. Our ultimate hope is that the functional characterization of ADRB2 in metastatic prostate cancer will one day lead to an effective therapy for this invariably lethal disease.