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The Type III TGF-Beta Receptor as a Candidate Tumor Suppressor Gene in Breast Cancer
Transforming growth factor-beta (TGF-beta) is a potent inhibitor of human mammary epithelial proliferation; most breast cancers become resistant to the growth inhibitory effects of TGF-beta through mechanisms that remain to be defined. The type III TGF-beta receptor (TbetaRIII) has a poorly understood role in TGF-beta signaling. In preliminary studies, we demonstrate that TbetaRIII mRNA is significantly decreased or lost in 89.3% (50/56) of human breast cancers; reintroducing TbetaRIII into breast cancer cell lines restores their TGF-beta responsiveness; the TbetaRIII genomic locus (1p32) is frequently lost in breast cancer (58.3%) and the TbetaRIII promoter contains several CpG islands, making it a potential target for silencing by hypermethylation. Based on these preliminary studies, we hypothesize that: Decreased TbetaRIII expression caused by genomic deletion and/or epigenetic silencing confers resistance to growth inhibitory effects of TGF-beta and promotes mammary carcinogenesis. This hypothesis will be addressed by three Specific Aims. Aim 1: The protein levels of TbetaRIII will be examined in different stage breast cancer specimens to determine whether loss of TbetaRIII expression is an early or late event during the sequential development of breast cancer. Aim 2: Promoter methylation and allelic imbalance studies will be performed to define the mechanism(s) of decreased TbetaRIII expression at the message level during mammary carcinogenesis. Aim 3: The effects of overexpressing TbetaRIII on MMTV-neu mediated breast tumorigenesis will be studied to determine whether TbetaRIII functions as a tumor suppressor in breast cancer. Study Design: 1. Surgically removed different stage human breast cancer and adjacent normal breast tissue will be analyzed for TbetaRIII expression by immunohistochemistry. 2. DNA will be extracted from breast cancer with decreased TbetaRIII expression and used for loss of heterozygosity and promoter methylation analysis. 3. Transgenic mice overexpressing TbetaRIII in the breast tissue will be generated and crossed to MMTV-neu murine model of breast cancer. The resulting bigenic mice will be analyzed for breast cancer tumorigenicity and metastatic potential to determine whether TbetaRIII functions as a tumor suppressor in breast cancer. Potential Outcomes and Benefits of the Research: These studies will define the role of TbetaRIII in mammary carcinogenesis; characterize the mechanism for its decreased expression and allow targeting of the TGF-beta signaling pathway for the chemoprevention and treatment of breast cancer.
Breast cancer is the second most common cause of cancer death in women claiming about 40,000 lives annually in the United States. Like other types of cancers, genetic alterations occurring in breast cancer cells are the major driving force of cancer development. These genetic alterations allow the cancer cells to become resistant to growth inhibitory signals and proliferate in an uncontrolled manner. Identifying such genetic alterations is essential for establishing better treatments of breast cancer. During the process of tumorigenesis most breast cancers become resistant to the growth inhibitory effects of transforming growth factor-beta (TGF-beta), a ubiquitous growth factor. However, the mechanism for this resistance has not been determined. The goal of this project is to characterize the mechanisms underlying TGF-beta resistance in breast cancer. One of the cell surface receptors for TGF-beta, the type III TGF-beta receptor (TbetaRIII) classically functions by binding to TGF-beta and enhancing binding of TGF-beta to the signaling receptors. In preliminary studies, we demonstrate that: 1. TbetaRIII was absent or significantly decreased in 89.3% (50/56) of human breast cancers compared to matching normal control tissue. 2. Reintroducing TbetaRIII into human breast cancer cell lines restores their responsiveness to TGF-beta. These data strongly suggest that TbetaRIII is a novel tumor suppressor, with reduction of TbetaRIII expression conferring resistance to TGF-beta mediated growth inhibition and promoting breast cancer development. To test these possibilities, we will examine whether overexpressing TbetaRIII in breast tissue can impair tumorigenesis using a well-established mouse model of breast cancer. We will also explore the mechanisms that lead to decreased TbetaRIII expression in breast cancer cells. These studies will fill a fundamental gap in terms of the mechanism of TGF-beta resistance in breast cancer, define the role of TbetaRIII in mammary carcinogenesis and allow targeting of the TGF-beta signaling pathway for the chemoprevention and treatment of human breast cancer.