Loss of Androgen Receptor Promotes Metastatic Prostate Cancer

雄激素受体的丧失会促进转移性前列腺癌

• 批准号: 7387676
• 负责人: CHAWNSHANG CHANG
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387676
• 关键词: Ablation; Adenocarcinoma; Androgen Antagonists; Androgen Receptor; Androgens; Cancer Etiology; Cancer Model; Cessation of life; Clinical; Complementary DNA; Development; Disseminated Malignant Neoplasm; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Gene Expression; Genes; Goals; Growth; Hormones; In Vitro; Invasive; Knock-out; Knockout Mice; Lead; Link; Liver; Liver neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Metastatic Prostate Cancer; Modality; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Numbers; PC3 cell line; Pelvic lymph node group; Play; Property; Prostate; Prostate Cancer therapy; Prostatic; Prostatic Neoplasms; RNA Interference; Regulation; Role; SCID Mice; Stromal Cells; Testing; Therapeutic; Transgenic Model; Transgenic Organisms; Tumor Cell Invasion; United States; Variant; Wild Type Mouse; Withdrawal; Xenograft procedure; base; bone; bone xenograft; concept; deprivation; foot; functional status; lymph nodes; men; mouse model; neoplastic cell; receptor expression; receptor function; success; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：该提案的总体目的是研究雄激素受体（AR）在前列腺癌转移中的作用。前列腺癌是美国男性与癌症相关死亡的第二大原因。据信，雄激素作用和AR的功能状态是前列腺癌发展的重要介体。尽管已知雄激素/AR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功能。已经对小鼠前列腺（Tramp）小鼠模型的转基因腺癌​​进行了初步研究，发现AR在前列腺上皮中的消融导致盆腔淋巴结（PLN）转移性肿瘤的较大盆腔淋巴结（PLN）转移性肿瘤的发展，并抑制了liver river retastic foci的liver river tumer tumer profors a prowsor a prowsor a prowsor a prowsor a prowsor a prowsor a profforce。因此，拟议的研究将使用具有不同AR表达的流浪汉小鼠和人类前列腺癌细胞系的各种ARKO模型，以研究AR在前列腺肿瘤转移中的抑制作用。最初将生成前列腺上皮特异性（PES）AR敲除（AIM 1）和可诱导的Arko Tramp小鼠（AIM 2），以研究PES-ARKO和ARKO的诱导，在前列腺肿瘤发生后，对PLN转移性肿瘤的形成和生长以及各种Meterated Metters servely cemants servely and and and and terressive servely and and centers and tercressiss cenes sypers cenes is cenasiss-ned natastasis-repers-repersiss-repersiss- repersiss repere n and teprated and teproct。随后，在AR阴性PLN肿瘤细胞中抑制AR表达（AR特异性RNA干扰）在AR阳性和恢复AR表达（与功能性AR cDNA）中的作用（功能性AR cDNA）以及各种人类前列腺癌细胞系（AIM 3）对转移相关基因的侵入性特性和表达水平的影响将在骨Xenogrys中均在骨Xenogrys中研究。最后，将研究AR调节各种转移相关基因表达水平的分子机制（AIM 4）。因此，该应用的成功无疑将发现AR作为前列腺癌进展过程中AR作为转移抑制剂的替代作用。 AR功能作为转移抑制剂的建立，并了解其如何调节肿瘤转移相关的基因，应导致治疗方式的新概念和用于前列腺癌治疗的分子靶向。 项目叙述：雄激素受体的丧失会促进转移性癌症。我们将研究前列腺上皮中雄激素受体的丧失以及这种损失对前列腺转移性肿瘤侵袭的影响。该应用的成功无疑将发现雄激素受体作为前列腺癌进展过程中转移抑制剂的替代作用。雄激素受体的建立功能是一种转移抑制剂，并了解它如何调节肿瘤转移相关的基因，应导致新的治疗概念和前列腺癌治疗的分子靶标。