Mechanism of PIN development in Abi1/Hssh3bp1 KO mouse

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的主要原因（今年约32，000例），也是美国男性中诊断的主要癌症（2012年约241，000例新发病例）。最近，新诊断的前列腺癌数量有所上升。这些令人震惊的统计数据需要临床医生，医疗保健提供者，科学界和资助机构的特别关注。不同的基因变化已被确定为导致男性前列腺癌。癌症患者肿瘤形成的常见机制之一是一种或多种所谓的肿瘤抑制基因失活。肿瘤抑制基因的失活对特定组织内细胞生长的调节具有破坏性后果，并导致肿瘤发展。我们的小组已经确定了一个这样的肿瘤抑制基因，Abi 1/Hssh 3bp 1，并开发了一种新的条件性敲除小鼠模型，以研究该基因在前列腺癌发生中的作用。前列腺特异性Abi 1/Hssh 3bp 1基因的破坏导致前列腺上皮内瘤变（PIN）的发展。鉴于我们公布的数据表明在Abil KO小鼠中观察到的前列腺病理学是异常调节的细胞间粘附和PI-3激酶-Akt途径活化的结果，该小鼠模型提供了急需的基于机制的动物模型，利用该动物模型进行Abil的肿瘤抑制作用以及其在导致前列腺癌的肿瘤过程的起始中的作用的详细研究。此外，我们在实验室中产生的其他小鼠模型的初步数据表明，Abi 1在前列腺癌中最常见的突变基因PTEN的下游起作用，并调节肿瘤侵袭。更好地了解Abi 1的功能可能会导致前列腺癌治疗的新治疗选择，并建立用于前列腺癌转化研究的新型小鼠模型。

DESCRIPTION (provided by applicant): Prostate cancer is the leading cause of male cancer-related deaths in the United States (about 32,000 this year) and the leading diagnosed cancer in American men (about 241,000 new cases in 2012). The number of new prostate cancer diagnoses has risen recently. These alarming statistics require special attention from clinicians, healthcare providers, scientific communities, and funding agencies. Different genetic changes have been identified to cause prostate cancer in men. One of the common mechanisms of tumor formation in cancer patients is inactivation of one or more so- called tumor suppressor genes. Inactivation of tumor suppressor genes has devastating consequences on the regulation of cell growth within a specific tissue and results in tumor development. Our group has identified one such tumor suppressor gene, Abi1/Hssh3bp1, and has developed a novel conditional knockout mouse model to study the role of this gene in development of prostate cancer. Prostate-specific disruption of the Abi1/Hssh3bp1 gene leads to development of prostatic intraepithelial neoplasia (PIN). Given our published data indicating that the observed prostate pathology in Abi1 KO mice is the result of abnormally regulated cell- to-cell adhesion and activation of PI-3 kinase-Akt pathway, this mouse model provides a much- needed mechanistically based animal model with which to conduct detailed studies of Abi1's tumor suppressive role as well as its role in the initiation of neoplastic processes leading to prostate cancer. Moreover, our preliminary data from additional mouse models generated in the lab indicate that Abi1 acts downstream from the most commonly mutated gene in prostate cancer, PTEN, and regulates tumor invasion. A better understanding of Abi1's function might lead to new therapeutic options for the treatment of prostate cancer and establishment of the novel mouse model for translational research in prostate cancer.