New Mice Models for Studies of Androgen Receptor in Prostate Cancer

描述（由申请人提供）：前列腺癌目前是美国男性的第二大癌症死亡。前列腺癌依赖于通过雄激素受体（AR）起作用的雄激素来生长和存活，并且雄激素消融已用于前列腺癌的治疗。尽管最初的反应良好，激素消融治疗最终失败，癌症进展为无法治愈的转移性疾病。关于前列腺癌遗传学的流行病学数据表明AR突变以及AR多聚谷氨酰胺（poly-Q）多态性在前列腺癌发展的易感性和对治疗的反应中的作用。该提案的总体目标是建立小鼠前列腺癌模型，用于研究AR在前列腺癌发展和转移中的作用。使用Cre-loxP条件性基因敲除技术，使用细胞类型特异性AR敲除（ARKO）的TRAMP或PTEN缺陷小鼠前列腺癌模型的几种衍生物（青春期后上皮细胞、成纤维细胞和平滑肌细胞特异性ARKO），用AR（T857 A）替代前列腺上皮AR [人AR（T877 A）的鼠等效物]将产生突变体用于体内研究AR在前列腺基质细胞或上皮细胞中的作用，AR（T877 A）突变在前列腺癌起始、进展或转移中的作用。将通过组织学分析、各种细胞标志物的免疫组织化学测定、肿瘤转移相关基因和蛋白质的表达水平的生物化学测定以及其转移性肿瘤的侵袭特性分析，检查这些模型中的前列腺肿瘤起始、进展和/或转移，并与表达野生型AR的同窝仔进行比较。通过各种ARKO或AR（T857 A）小鼠及其野生型同窝小鼠之间这些参数的差异，将描述AR在每种特定细胞类型中的作用以及AR（T877 A）突变在前列腺癌发生中的作用。从这些研究中获得的信息不仅将提供更好地了解AR在前列腺癌发生中的作用，而且将有助于设计新的治疗方案用于激素难治性前列腺癌。此外，这些模型可能有助于测试前列腺癌治疗的新药。项目叙述：研究前列腺癌雄激素受体的新小鼠模型 我们将产生各种小鼠模型，这些模型在前列腺的单个细胞中缺乏雄激素受体，并研究它们对前列腺癌进展的影响。从我们对这些小鼠模型之间差异的研究中获得的信息将使我们了解雄激素受体在前列腺癌发展中的一些作用，也将有助于设计前列腺癌的新治疗方法。此外，这些小鼠模型可能有助于测试前列腺癌治疗的新药和治疗方法，最终可能用于人类。

DESCRIPTION (provided by applicant): Prostate cancer is currently the second leading cancer death in American men. Prostate cancer is dependent on androgen acting through the androgen receptor (AR) for growth and survival, and androgen ablation has been used for treatment of prostate cancer. Despite an initially favorable response, hormone ablation therapy eventually fails and the cancer progresses to an incurable metastatic disease. Epidemiological data regarding prostate cancer genetics indicate roles of AR mutation, as well as AR poly-glutamine (poly-Q) polymorphism, in susceptibility to prostate cancer development and response to therapy. The overall objective of this proposal is to create mouse prostate cancer models for studying the role of the AR in prostatic cancer development and metastasis. Using the Cre-loxP conditional gene knockout technology, several derivatives of TRAMP or PTEN-deficient mouse prostate cancer models with cell type-specific AR knockout (ARKO) (post-puberty epithelial, fibroblast-, and smooth muscle cell-specific ARKO), replacement of prostatic epithelial AR with AR(T857A) [murine equivalent of human AR(T877A)] mutant will be generated for in vivo study of the roles of the AR in prostate stromal cells or epithelial cells, the AR(T877A) mutation in prostate cancer initiation, progression, or metastasis. Prostate tumor initiation, progression, and/or metastasis in these models will be examined and compared with their littermates expressing wild type AR through histological analyses, immunohistochemical determination of various cellular markers, biochemical determination of the expression levels of tumor metastasis related genes and proteins, and analysis of invasive properties of their metastatic tumor. Through the differences in these parameters between the various ARKO or AR (T857A) mice and their wild type littermates, the role of the AR in each specific cell type and the AR(T877A) mutation in prostate carcinogenesis will be delineated. Information obtained from these studies not only will provide better understanding of the roles of the AR in prostate carcinogenesis, but also will be useful for designing new treatment regimen for prostate cancer in hormone refractory state. In addition, these models may be useful for testing new drugs for prostate cancer therapy. Project Narrative: New Mice Models for Studies of Androgen Receptor in Prostate Cancer We will generate various mouse models that lack the androgen receptor in individual cells of the prostate and study their influence on prostate cancer progression. Information obtained from our studies of the differences between these mice models will lead to our understanding some roles of the androgen receptor in the development of prostate cancer and also will be useful for designing new treatments for prostate cancer. In addition, these mice models may be useful for testing new drugs and treatments for prostate cancer therapy, which might eventually be used in humans.