functions as a tumor suppressor early in tumorigenesis, but acts as a promoter of cancer progression. This dichotomous nature highlights the importance of the TGF- signaling pathway in cancer research and the need to precisely define how the pathway is regulated. The TGF- receptor III (T RIII) has been identified as an important mediator of TGF- signaling, functioning to suppress breast cancer progression through the inhibition of TGF- signaling, cancer cell invasion, and metastasis. T RIII functions, in part, through production of the soluble form of T RIII, which inhibits TGF- signaling. In addition, T RIII expression is progressively lost during breast cancer progression, with decreased T RIII levels correlating with reduced patient survival. Similarly, cell polarity is often lost during cancer progression, which may be mediated by epithelial-mesenchymal transition (EMT). Interestingly, the EMT process is triggered by TGF- and inhibited by T RIII in breast epithelial cells. My preliminary results indicate that T RIII is localized to basolateral cell-cell junctions in normal polarized breast epithelial cells. As components of adherens junctions have been demonstrated to interact with other TGF- receptors, I hypothesize that localization of T RIII at cell-cell junctions is dependent upon the presence of adherens junctions, and that mislocalization of T RIII will result in increases in TGF- signaling and an increased susceptibility of normal and breast epithelial cells to EMT, subsequently leading to increases in cell migration and invasion in vitro and increases in metastasis in vivo. This hypothesis will be addressed by three specific aims: SA1. Define the region of T RIII that mediates basolateral membrane targeting and establish whether adherens junction formation is necessary for the basolateral localization of T RIII, SA2. Determine whether disruption of the basolateral localization of T RIII affects TGF- signaling or is sufficient to result in biological effects that are associated with cancer progression, and SA3. Establish if mislocalization of T RIII affects the growth, cellular invasiveness, or metastatic potential of breast cancer cells in a murine model for mammary carcinogenesis. These studies will enhance our understanding of the regulation of T RIII and TGF- signaling during breast cancer progression, increasing our ability to assess and target this pathway for the benefit of cancer patients.

Public Health Relevance

We have demonstrated that a cell surface receptor for the transforming growth factor-2 (TGF-2), the type III TGF-2 receptor (T2RIII), is able to suppress cancer progression in a broad spectrum of human cancers, including cancers of the breast, lung, ovary, pancreas and prostate, by decreasing the ability of the cancer cells to migrate, invade and spread to distant sites. As T2RIII can mediate these effects both through regulation of TGF-2 signaling as well as through TGF-2 signaling-independent mechanisms, a more precise understanding of the role of the T2RIII in mammary carcinogenesis is required to target both T2RIII and the TGF-2 signaling pathway for the treatment of human breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F09-E (20))
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Jakowlew, Sonia B
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Meyer, Alison E; Gatza, Catherine E; How, Tam et al. (2014) Role of TGF-? receptor III localization in polarity and breast cancer progression. Mol Biol Cell 25:2291-304