乳腺癌是女性最常见的恶性肿瘤之一，寻找乳腺癌易感生物标志物是国际上预防、诊断和靶向治疗的热点。经过多年的研究，我们利用大鼠乳腺肿瘤动物模型和遗传连锁分析，在大鼠上定位并初步识别和确定Furry homolog (Drosophila) 基因(FRY)，为全新的乳腺癌肿瘤抑癌基因。在这些前期工作的基础上，本项目拟通过体外和体内致癌试验, 进一步研究FRY基因与乳腺肿瘤发展和恶性变间的关系。并利用基因敲除技术构建FRY基因全敲除和乳腺特异敲除小鼠，来确证FRY基因的分子功能和确定FRY基因缺失与乳腺肿瘤发展的关系。在此基础上，并运用蛋白质组学和基因组学等技术，识别与FRY基因相互作用的靶基因和细胞信号通路，确定FRY基因抑癌的内在分子机制。这些结果将为最终应用FRY基因作为乳腺癌诊断和治疗反应及预后预测的生物标志物，以及作为治疗乳腺癌的靶向位点提供理论基础。

Breast cancer remains the most prevalent cancer among women. Although numerous genetic alterations and molecular pathways are implicated in the pathogenesis of breast cancer, significant gaps remain in our knowledge regarding the biology, etiology, and genetic susceptibility to this disease. Genetic factors play a vital role in the development and the overall genetic susceptibility of breast cancer. However, genetic linkage studies in high-risk families identified BRCA1 and BRCA2, which are implicated in less than 10% of all breast cancers and account for only a fraction of familial breast cancers. Thus, it is critical to identify other genetic risk factors that modify the susceptibility of breast cancer, which can lead to a new, genetic, era of prediction, prevention, and treatment for breast cancer...Human linkage analysis is complicated and difficult, even in high-risk families; we thus applied an alternative approach to identifying breast cancer susceptibility genes by conducting linkage analysis in inbred rat mammary tumor models. Using this strategy, we identified FRY as a putative mammary carcinoma susceptibility gene. FRY, the first putative human tumor suppressor discovered by linkage analysis in rodents, suppresses tumor growth and invasiveness of human tumor cells in nude mice, and its decreased expression and nuclear localization decreased in human breast, cancers are associated with more aggressive histopathological phenotypes and poor clinical outcomes. ..However, there remain significant gaps in our understanding of the molecular mechanisms of FRY in inhibiting breast cancer development and progression. We thus propose to conduct a series of in vitro and in vivo carcinogenesis assay to further test the capacity of FRY in suppressing the growth and invasiveness of different types of breast cancer. Moreover, we propose to generate FRY constitutive knockout and mammary tissue conditional knockout mice. These knockout mice will act as the important tool for studying the biological role of FRY gene and its association with the development of breast cancer. In addition, we will utilize genomic and proteomic approach to identify potential partners in FRY associated cell signaling cascades and thus understand the biological function of FRY and its role in tumor development. ..We expect that findings from this study will provide convincing data that FRY may represent a new target for cancer screening, therapeutic interventions targeting epithelial cancers, and gene therapy.