Role of TGF beta receptor III localization in breast cancer progression

描述(申请人提供)：在肿瘤形成的早期发挥肿瘤抑制因子的作用，但作为癌症进展的促进剂。这种二分性突出了转化生长因子信号通路在癌症研究中的重要性，以及精确定义该通路是如何调控的需要。转化生长因子受体III(TRIII)被认为是转化生长因子信号的重要介体，通过抑制转化生长因子信号，抑制癌细胞侵袭和转移，从而抑制乳腺癌的进展。TRIII的功能部分是通过产生可溶形式的TRIII来发挥作用的，这种形式抑制了转化生长因子信号转导。此外，在乳腺癌进展过程中，T RIII的表达逐渐丢失，T RIII水平的降低与患者存活率的降低相关。类似地，细胞极性通常在癌症进展过程中丢失，这可能是由上皮-间充质转化(EMT)所介导的。有趣的是，乳腺上皮细胞中的EMT过程是由转化生长因子-α触发的，并被T-RIII抑制。我的初步结果表明，在正常极化的乳腺上皮细胞中，TRIII定位于基侧细胞-细胞连接。由于黏附连接的成分已被证明与其他转化生长因子受体相互作用，我假设T受体III在细胞-细胞连接的定位取决于黏附连接的存在，并且T受体III的错误定位将导致转化生长因子信号的增加和正常乳腺上皮细胞对EMT的敏感性增加，从而导致细胞在体外的迁移和侵袭增加以及体内转移的增加。这一假设将通过三个具体目标来解决：SA1。确定介导基侧膜靶向的T RIII区域，并确定粘连连接的形成是否对T RIII、SA2的基侧定位是必要的。确定TRIII基侧定位的中断是否影响转化生长因子信号转导，或者是否足以导致与癌症进展和SA3相关的生物学效应。在乳腺癌发生的小鼠模型中，确定TRIII的错误定位是否会影响乳腺癌细胞的生长、细胞侵袭或转移潜能。这些研究将加深我们对乳腺癌进展过程中TRIII和转化生长因子信号的调控的理解，提高我们评估和定位这一途径以造福于癌症患者的能力。

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.