Elucidating the Role of the TGF-Beta Receptor III in Breast Carcinogenesis

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DESCRIPTION (provided by applicant): Further understanding the role of the TGF-¿ signaling pathway in breast carcinogenesis will lead to the identification of new human therapeutic treatments. TGF-¿ signaling is regulated in part by a co-receptor, the type III TGF-¿ receptor (T¿RIII). In addition, soluble T¿RIII (sT¿RIII), which is generated through ectodomain shedding of the T¿RIII receptor, inhibits TGF-¿ signaling by sequestering ligand, resulting in the down-regulation of TGF-¿ mediated signaling. In early stage breast tumors TGF-¿ functions as a tumor suppressor, while in late-stage tumors TGF-¿ signaling has a tumor promoting effect. The loss of T¿RIII expression is a frequent early event in human breast cancers and the restoration of T¿RIII expression inhibits tumor invasion, angiogenesis, and metastasis, supporting T¿RIII as a tumor suppressor in breast cancer. The tumor suppressor function of T¿RIII appears to be due, in part, to the generation of sT¿RIII, which antagonizes the tumor promoting effects of TGF-¿ signaling in late stage mammary tumors. However, this suggests that increasing T¿RIII expression prior to the initiation of mammary carcinogenesis may promote tumorigenesis due to the increased expression of sT¿RIII and subsequent down-regulation of TGF-¿ signaling. Conversely, during late-stage mammary tumors, T¿RIII, through sT¿RIII production, inhibits tumor progression by limiting tumor invasion and migration. This study aims to determine the role of T¿RIII in mammary gland development and to further characterize its effects on the initiation and progression of mammary carcinogenesis by utilizing the MMTV-T¿RIII mouse model, which over-expresses T¿RIII in the mammary gland. This will be addressed by four specific aims: (1) Establish whether MMTV-T¿RIII mice exhibit accelerated mammary gland development. (2) Establish whether MMTV-T¿RIII mice exhibit elevated circulating levels of sT¿RIII and decreased TGF-¿ signaling. (3) Establish whether increased T¿RIII expression promotes mammary cancer initiation, but inhibits cancer progression through the assessment of oncogene (cross to MMTV-her2/neu mice) and chemical carcinogen (DMBA) induced tumorigenesis in MMTV-T¿RIII mice. (4) Establish whether T¿RIII exerts its inhibitory effects on tumor progression through the inhibition of directed migration and invasion. PUBLICL HEALTH RELEVANCE: Defining the role of the T¿RIII in mammary carcinogenesis will identify it as a potential therapeutic target for the treatment of human breast cancer. These studies will determine the effects of T¿RIII over-expression on breast cancer initiation and progression, identify T¿RIII and sT¿RIII as potential targets for human therapeutic treatments, and aid in targeting of the TGF-¿ signaling pathway for the treatment of various stages of human breast cancers.