Loss of Androgen Receptor Promotes Metastatic Prostate Cancer

描述（由申请人提供）：本提案的总体目标是研究雄激素受体（AR）在前列腺癌转移中的作用。前列腺癌是美国男性癌症相关死亡的第二大原因。雄激素的作用和AR的功能状态被认为是前列腺癌发展的重要介质。虽然已知雄激素/AR可促进雄激素依赖性前列腺肿瘤的生长，但目前尚不清楚其在肿瘤转移中的作用。在转基因前列腺腺癌小鼠（TRAMP）前列腺癌小鼠模型中进行的初步研究发现，消融前列腺上皮中的AR可导致更大的盆腔淋巴结（PLN）转移瘤和更多的肝转移灶，提示AR可能具有抑制前列腺肿瘤转移的作用。因此，本研究将利用不同AR表达的TRAMP小鼠和人前列腺癌细胞系的各种ARKO模型来研究AR对前列腺肿瘤转移的抑制作用。首先将产生前列腺上皮特异性（pes） AR敲除（ARKO） （Aim 1）和ARKO诱导TRAMP小鼠（Aim 2），研究前列腺肿瘤发生后pes-ARKO和ARKO诱导对PLN转移性肿瘤形成和生长以及各种转移相关基因表达水平的影响。随后，我们将在体外和异种骨移植SCID小鼠中研究在AR阳性细胞中抑制AR表达（通过AR特异性RNA干扰）和在AR阴性的PLN肿瘤细胞和各种人前列腺癌细胞系（Aim 3）中恢复AR表达（通过功能性AR cDNA）对其侵袭特性和转移相关基因表达水平的影响。最后，研究AR调控各种转移相关基因表达水平的分子机制（Aim 4）。因此，这项应用的成功无疑将揭示AR在前列腺癌进展过程中作为转移抑制因子的另一种作用。建立AR作为转移抑制因子的功能，了解其如何调节肿瘤转移相关基因，将为前列腺癌的治疗方式和分子靶向治疗带来新的概念。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the role of the androgen receptor (AR) in prostate cancer metastasis. Prostate cancer is the second leading cause of cancer-related death among men in the United States. Androgen action and the functional status of the AR are believed to be the important mediators of prostate cancer development. Although androgen/AR is known to promote growth of androgen-dependent prostate tumors, its function in tumor metastasis is unclear at present. A preliminary study has been made in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models of prostate cancer and discovered that ablation of the AR in prostate epithelium resulted in development of larger pelvic lymph node (PLN) metastatic tumors and higher numbers of liver metastatic foci, suggesting that AR might function as a suppressor of prostate tumor metastasis. Therefore, the proposed studies will use various ARKO models of TRAMP mice and human prostate cancer cell lines with different AR expression to investigate the suppressor role of AR in prostate tumor metastasis. Initially prostate epithelium-specific (pes) AR knockout (ARKO) (Aim 1) and inducible ARKO TRAMP mice (Aim 2) will be generated to study the effect of pes-ARKO and induction of ARKO, after prostate tumors have developed, on PLN metastatic tumor formation and growth as well as the expression levels of various metastasis-related genes. Subsequently, the effect of suppressing AR expression (with AR-specific RNA interference) in AR-positive and restoring AR expression (with functional AR cDNA) in AR-negative PLN tumor cells and various human prostate cancer cell lines (Aim 3) on their invasive properties and expression levels of metastasis-related genes will be studied in vitro as well as in bone xenografts in SCID mice. Finally, the molecular mechanisms through which AR regulates the expression levels of various metastasis-related genes will be studied (Aim 4). Therefore, the success of this application undoubtedly will uncover an alterative role of the AR as a metastasis suppressor during prostate cancer progression. The establishment of the AR function as a metastasis suppressor and understanding of how it regulates tumor metastasis-related genes, should lead to new concepts of treatment modality and molecular targeting for prostate cancer therapy. Project Narrative: Loss of Androgen Receptor Promotes Metastatic Cancer. We will study the loss of androgen receptor in prostate epithelium and the influence of this loss on prostatic metastatic tumor invasion. The success of this application undoubtedly will uncover an alterative role of the androgen receptor as a metastasis suppressor during prostate cancer progression. The establishment of the androgen receptor function as a metastasis suppressor and understanding of how it regulates tumor metastasis-related genes, should lead to new concepts of treatments and molecular targets for prostate cancer therapy.