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