Role of TGF beta receptor III localization in breast cancer progression

TGFβ受体III定位在乳腺癌进展中的作用

基本信息

批准号：
8337521
负责人：
Alison Meyer
金额：
$ 5.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2014-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337521
关键词：
Address Adherens Junction Affect Antibodies Apoptosis Binding Biological Biological Assay Bone Morphogenetic Proteins Breast Breast Cancer Cell Breast Carcinoma Cancer Patient Cancer cell line Cell Migration Pathway Cell Polarity Cell Surface Receptors Cell surface Cells Distant E-Cadherin Egtazic Acid Epithelial Epithelial Cells Genes Growth Growth Factor Human In Vitro Intercellular Junctions Invaded Ligands Luciferases Lung Maintenance Malignant Neoplasms Mammary Tumorigenesis Mediating Mediator of activation protein Membrane Mesenchymal Modeling Monitor Mus Nature Neoplasm Metastasis Normal tissue morphology Ovarian Ovary Pancreas Pathway interactions Patients Phosphorylation Play Predisposition Primary Neoplasm Process Production Prostate Proteins Regulation Reporter Role Signal Pathway Signal Transduction Site Source Staging Structure Survival Rate Transforming Growth Factor beta Receptors Transforming Growth Factors Tumor Promoters Tumor Suppressor Proteins angiogenesis anticancer research base basolateral membrane cancer cell cell growth cell motility epithelial to mesenchymal transition in vivo malignant breast neoplasm mouse model mutant overexpression polarized cell promoter receptor tumor tumor progression tumorigenesis wound

项目摘要

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.

描述（由申请人提供）：在肿瘤发生早期充当肿瘤抑制因子，但充当癌症进展的促进剂。这种二分性凸显了 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 (T RIII) 已被确定为 TGF-信号传导的重要介质，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。 T RIII 的部分功能是通过产生可溶形式的 T RIII，从而抑制 TGF 信号传导。此外，在乳腺癌进展过程中，T RIII 表达逐渐丧失，T RIII 水平降低与患者生存率降低相关。同样，细胞极性在癌症进展过程中经常会丢失，这可能是由上皮间质转化（EMT）介导的。有趣的是，乳腺上皮细胞中的 EMT 过程由 TGF-β 触发，并由 T RIII 抑制。我的初步结果表明，T RIII 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-细胞连接处的定位取决于粘附连接的存在，并且 T RIII 的错误定位将导致 TGF-β 受体的增加。信号传导以及正常和乳腺上皮细胞对 EMT 的敏感性增加，随后导致体外细胞迁移和侵袭增加以及体内转移增加。这一假设将通过三个具体目标来解决：SA1。定义介导基底外侧膜靶向的 T RIII 区域，并确定粘附连接的形成对于 T RIII、SA2 的基底外侧定位是否是必要的。确定 T RIII 基底外侧定位的破坏是否会影响 TGF-信号传导或足以导致与癌症进展和 SA3 相关的生物效应。确定 T RIII 的错误定位是否会影响小鼠乳腺癌模型中乳腺癌细胞的生长、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 信号传导调节的理解，提高我们评估和靶向该通路的能力，从而造福癌症患者。