Role of TGF beta receptor III localization in breast cancer progression

描述（由申请人提供）：在肿瘤发生的早期作为肿瘤抑制剂发挥作用，但作为癌症进展的促进剂发挥作用。这种二分法的性质突出了TGF-信号通路在癌症研究中的重要性，以及精确定义该通路如何调节的必要性。TGF-受体III（TRIII）已被鉴定为TGF-信号传导的重要介体，其通过抑制TGF-信号传导、癌细胞侵袭和转移来抑制乳腺癌进展。TRIII部分地通过产生抑制TGF-β信号传导的可溶形式的TRIII起作用。此外，在乳腺癌进展期间，TRIII表达逐渐丧失，其中降低的TRIII水平与降低的患者存活率相关。类似地，在癌症进展期间细胞极性常常丧失，这可能由上皮-间充质转化（EMT）介导。有趣的是，在乳腺上皮细胞中，EMT过程由TGF-β触发并由TRIII抑制。我的初步结果表明，TRIII是本地化的基底外侧细胞细胞连接正常极化乳腺上皮细胞。由于粘附连接的组分已被证明与其他TGF-受体相互作用，因此我假设细胞-细胞连接处的TRIII定位依赖于粘附连接的存在，并且TRIII的错误定位将导致TGF-信号传导的增加和正常和乳腺上皮细胞对EMT的易感性增加，随后导致体外细胞迁移和侵袭的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：SA 1。定义介导基底外侧膜靶向的TRIII区域，并确定粘附连接形成是否是TRIII、SA 2的基底外侧定位所必需的。确定TRIII基底外侧定位的破坏是否影响TGF-β信号传导或足以导致与癌症进展和SA 3相关的生物学效应。在乳腺癌发生的鼠模型中，确定TRIII的错误定位是否影响乳腺癌细胞的生长、细胞侵袭力或转移潜力。这些研究将增强我们对乳腺癌进展过程中TRIII和TGF-β信号传导调节的理解，提高我们评估和靶向这一途径的能力，以造福癌症患者。

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.