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

描述（由申请人提供）：编码TGFbl信号通路组分的基因，包括TGFB1和TGFBRI，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，TGFbl对许多不同的细胞类型具有多效性，对肿瘤发生的影响可能是正的，也可能是负的，因此不同的人类遗传关联研究往往得出不同的结论。在皮肤肿瘤发生的小鼠模型中，研究表明，与过度活跃的Tgfbl等位基因相关的肿瘤易感性依赖于Tgfbl基因与非连锁变异体皮肤肿瘤易感性位点SktslS的遗传相互作用。TGFbl基因敲除小鼠的遗传连锁分析之前已经独立地鉴定出Skts15区域是TGFbl相互作用位点TgfbmS。该项目的总体目标是确定Tgfbl和Skts15/Tgfbm3相互作用以确定小鼠癌症易感性的生物学和分子机制，并阐明TGFB1和Tgfbm3 / Skts15之间类似的遗传相互作用是否会改变人类的癌症风险。一组Skts15/Tgfbm3基因座C57（或spretus）的NIH小鼠将用于验证和精细绘制Skts15/Tgfbm3肿瘤易感性基因，并研究导致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影响、炎症、免疫监视和肿瘤血管生成。一项人类遗传关联研究将在一项针对女性乳腺癌的大型病例对照研究中进行，重点研究SKTS15/TGFBM3内的基因及其与TGFB1和其他关键TGFbeta信号组分的潜在相互作用。TGFb通路抑制剂用于治疗转移性癌症的临床试验的开始反映了TGFb信号传导对癌症进展和扩散的重要性。然而，tgfbl介导的肿瘤进展中涉及的确切生物学和分子途径仍有待了解；对这些新药的精细化开发至关重要的信息。从该项目中获得的信息：a)将增加对tgfβ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tgfβ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