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

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

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