New Mice Models for Studies of Androgen Receptor in Prostate Cancer

用于研究前列腺癌雄激素受体的新小鼠模型

• 批准号: 7996057
• 负责人: CHAWNSHANG CHANG
• 金额: $ 31万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996057
• 关键词: AR gene; Ablation; Address; Agonist; American; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Biochemical Markers; Biometry; Breeding; Cancer Model; Cells; Cessation of life; Data; Development; Disease; Epidemiology; Epithelial; Epithelial Cells; Estrogens; Fibroblasts; Gene Deletion; Gene Expression Profile; Gene Proteins; Genetic Polymorphism; Growth; Hormones; Human; Incidence; Individual; Knock-in Mouse; Knock-out; Knockout Mice; LNCaP; Lead; Letters; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic to; Methods; Modeling; Monitor; Mus; Mutation; Neoplasm Metastasis; PTEN gene; Penetrance; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Property; Prostate; Prostate Cancer therapy; Prostatic; Prostatic Neoplasms; Protein Analysis; Puberty; Recommendation; Refractory; Role; Smooth Muscle Myocytes; Staging; Stromal Cells; System; Technology; Testing; Transgenic Mice; Treatment Protocols; cancer cell; cancer genetics; cancer initiation; cell type; design; experience; hydroxyflutamide; in vivo; knockout gene; men; mouse model; mutant; polyglutamine; pre-clinical; prostate carcinogenesis; receptor; receptor function; research study; response; tumor; tumor initiation; tumor progression

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.

描述（由申请人提供）：前列腺癌目前是美国男性第二大癌症死亡原因。前列腺癌的生长和存活依赖于雄激素通过雄激素受体 (AR) 发挥作用，雄激素消除已用于治疗前列腺癌。尽管最初反应良好，但激素消融疗法最终失败，癌症发展为无法治愈的转移性疾病。有关前列腺癌遗传学的流行病学数据表明，AR 突变以及 AR 聚谷氨酰胺 (poly-Q) 多态性在前列腺癌发展的易感性和治疗反应中的作用。该提案的总体目标是创建小鼠前列腺癌模型，用于研究 AR 在前列腺癌发展和转移中的作用。使用 Cre-loxP 条件基因敲除技术，TRAMP 或 PTEN 缺陷小鼠前列腺癌模型的几种衍生物具有细胞类型特异性 AR 敲除 (ARKO)（青春期后上皮细胞、成纤维细胞和平滑肌细胞特异性 ARKO），将产生用 AR(T857A) [人 AR(T877A) 的小鼠等效物]突变体替代前列腺上皮 AR，用于体内研究 AR 在前列腺基质中的作用细胞或上皮细胞中，前列腺癌发生、进展或转移中的 AR(T877A) 突变。将通过组织学分析、各种细胞标记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化测定，检查这些模型中前列腺肿瘤的发生、进展和/或转移，并与表达野生型AR的同窝动物进行比较。并分析其转移性肿瘤的侵袭特性。通过各种 ARKO 或 AR (T857A) 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(T877A) 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有助于更好地了解 AR 在前列腺癌发生中的作用，而且有助于设计针对激素难治状态的前列腺癌的新治疗方案。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：用于研究前列腺癌雄激素受体的新小鼠模型 我们将生成前列腺单个细胞中缺乏雄激素受体的各种小鼠模型，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有助于我们了解雄激素受体在前列腺癌发展中的某些作用，也将有助于设计前列腺癌的新疗法。此外，这些小鼠模型可能有助于测试前列腺癌治疗的新药物和疗法，最终可能用于人类。