"Genetic interactions between Tgfb1 and Skts15/Tgfbm3 in cancer"

描述（由申请人提供）：编码TGF β 1信号传导途径组分（包括TGF β 1和TGF β 1）的基因在人类中具有功能多态性，特定变体的携带状态决定了人类癌症风险。然而，TGF β 1对许多不同的细胞类型具有多效性活性，并且可以对肿瘤发生具有积极和消极的影响，因此不同的人类遗传关联研究经常导致不同的结论。在皮肤肿瘤发生的小鼠模型中，已经显示与过度活跃的Tgfbl等位基因相关的肿瘤易感性依赖于Tgfbl基因与非连锁变体皮肤肿瘤易感性基因座SktslS的遗传相互作用。TGFbl敲除小鼠的遗传连锁分析先前已独立地鉴定Skts 15区域为Tgfbl相互作用基因座TgfbmS。该项目的总体目标是确定Tgfbl和Skts 15/Tgfbm 3相互作用的生物学和分子机制，以确定小鼠的癌症易感性，并阐明TGFB 1和TGFBM 3/SKTS 15之间相似的遗传相互作用是否会改变人类的癌症风险。一组NIH小鼠，在Skts 15/Tgfbm 3基因座上与C57（或spretus）同源，将用于验证和精细定位Skts 15/Tgfbm 3，以鉴定肿瘤易感性基因，并研究有助于这种改变的肿瘤易感性的生物学参数。参数将包括对肿瘤细胞和宿主组织的生长和凋亡效应、炎症、免疫监视和肿瘤血管生成。将在一项针对乳腺癌女性的大型病例对照研究中进行人类遗传关联研究，重点关注SKTS 15/TGFBM 3内的基因及其与TGFB 1和其他关键TGF β信号传导组分的潜在相互作用。TGFb 1信号传导对癌症进展和扩散的重要性通过TGFb途径抑制剂用于治疗转移性癌症的临床试验的开始而反映。然而，关于TGF β 1介导的肿瘤进展所涉及的精确生物学和分子途径，还有很多东西有待了解;这些新药的精细开发的重要信息。从该项目中获得的信息：a）将增加对TGF β 1介导的肿瘤进展的生物学和分子途径的了解，B）可能有助于评估人类癌症风险的筛选工具c）可能为抗癌药物开发提供新的靶点或指示某些组合靶点d）可能有助于设计抗TGF β癌症治疗的个性化药物

DESCRIPTION (provided by applicant): Genes encoding components of the TGFbl signaling pathway including TGFB1 and TGFBRI are functionally polymorphic in humans, and carrier status of specific variants determines human cancer risk. However, TGFbl has pleiotropic activity on many different cell types, and can have both positive and negative effects on tumorigenesis, thus different human genetic association studies have often resulted in divergent conclusions. In a mouse model of skin tumorigenesis, it has been shown that tumor susceptibility associated with a hyperactive Tgfbl allele is dependent on genetic interaction of the Tgfbl gene with an unlinked variant skin tumor susceptibility locus, SktslS. Genetic linkage analysis of TGFbl knock out mice had previously independently identified the Skts15 region as a Tgfbl-interacting locus, TgfbmS. The overall goal of this project is to determine the biological and molecular mechanisms whereby Tgfbl and Skts15/Tgfbm3 interact to determine cancer susceptibility in mice, and to elucidate whether similar genetic interactions between TGFB1 and TGFBM3/SKTS15 alter cancer risk in humans. A panel of NIH mice, congenic for C57 (or spretus) at the Skts15/Tgfbm3 locus, will be used to validate and finely map Skts15/Tgfbm3 for identification of tumor susceptiblity genes, and to investigate the biological parameters that contribute to this altered tumor susceptibility. Parameters will include growth and apoptosis effects on the tumor cell and host tissues, inflammation, immune surveillance and tumor angiogenesis. A human genetic association study will be performed in a large case control study of women with breast cancer, focusing on genes within SKTS15/TGFBM3 and their potential interaction with TGFB1, and other key TGFbeta signaling components. The importance of TGFbl signaling to cancer progression and spread is reflected by the commencement of clinical trials of TGFb pathway inhibitors for treatment of metastatic cancers. Yet much still remains to be learnt about the precise biological and molecular pathways involved in TGFbl-mediated tumor progression; essential information to the refined development of these new drugs. The information gained from this project: a) Will add to knowledge on the biological and molecular pathways of TGFbl-mediated tumor progression, b) May contribute to screening tools for assessment of cancer risk in humans c) May provide new targets or indicate certain combinatorial targets for anti-cancer drug development d) May contribute to design of personalized medicines for anti-TGFbeta cancer therapies