Role of TGF beta receptor III localization in breast cancer progression

描述（由申请人提供）：在肿瘤发生早期作为肿瘤抑制因子，但作为癌症进展的促进剂。这种二分性突出了TGF-信号通路在癌症研究中的重要性，以及精确定义该通路调控方式的必要性。TGF-受体III （T RIII）已被确定为TGF-信号的重要介质，通过抑制TGF-信号、癌细胞侵袭和转移来抑制乳腺癌的进展。T RIII的部分功能是通过产生可溶形式的T RIII来抑制TGF-信号传导。此外，在乳腺癌进展过程中，T - RIII的表达逐渐丧失，T - RIII水平的降低与患者生存率的降低相关。同样，在癌症进展过程中，细胞极性经常丢失，这可能是由上皮-间质转化（EMT）介导的。有趣的是，乳腺上皮细胞的EMT过程是由TGF-触发并被Tⅲ抑制的。我的初步结果表明，triii定位于正常极化乳腺上皮细胞的基底外侧细胞-细胞连接处。由于粘附连接的成分已被证明与其他TGF-受体相互作用，我假设T RIII在细胞-细胞连接处的定位依赖于粘附连接的存在，T RIII的错误定位将导致TGF-信号的增加和正常上皮细胞和乳腺上皮细胞对EMT的易感性增加，从而导致细胞在体外迁移和侵袭增加，体内转移增加。这一假设将通过三个具体目标来解决：确定介导基底外侧膜靶向的triii区域，并确定粘附连接的形成对于triii基底外侧定位是否必要，SA2。确定Tⅲ基外侧定位的破坏是否会影响TGF-信号，或是否足以导致与癌症进展和SA3相关的生物学效应。在小鼠乳腺癌模型中，确定T iii的错误定位是否会影响乳腺癌细胞的生长、细胞侵袭性或转移潜力。这些研究将增强我们对乳腺癌进展过程中T RIII和TGF-信号调控的理解，提高我们评估和靶向这一途径的能力，造福癌症患者。

DESCRIPTION (provided by applicant): 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.