TBX3蛋白通过TGF-β/Wnt信号促进乳腺癌细胞EMT与侵袭的机理研究

转移是乳腺癌病人高死亡率的最主要原因；表皮细胞-间质细胞转变（EMT）与乳腺癌细胞侵袭和转移密切相关；TGF-β和Wnt信号在EMT诱导中发挥关键作用。研究显示：TBX3基因在一部分乳腺癌细胞系中高表达，并与癌细胞增殖和迁移相关。但是，TBX3在TGF-β/Wnt诱导的乳腺上皮细胞EMT、乳腺癌细胞侵袭与转移中的功能与机制仍不清楚。我们的前期研究显示TBX3在乳腺上皮细胞中可能通过反馈机制促进TGF-β/Wnt诱导的EMT；建立了乳腺癌细胞小鼠体内转移模型。在此项目中，我们拟利用多学科技术手段和小鼠乳腺癌转移模型，研究TBX3对TGF-β和Wnt信号的反馈调控作用与机制，阐明TBX3促进EMT和乳腺癌侵袭与转移的机理。相关成果有助于理解细胞转分化（EMT）、乳腺癌细胞侵袭与转移的分子基础。申请人在国际主流SCI期刊发表论文20余篇，总引用超600次数。

Metastasis is the major reason behind breast cancer-related death. TGF-β and Wnt play a crucial role in epithelial-mesenchymal transition (EMT), which has been proven closely involved in cell migration, invasion and metastasis in breast cancer. It has been found that TBX3 gene is overexpressed in a series of breast cancer cell lines, and is related to cancer cell proliferation and invasion. However, how TBX3 affects TGF-β- and Wnt-induced EMT and breast cancer invasion and metastasis remains elusive. We found in previous studies that TGF-β and Wnt coordinate TBX3 gene expression in the normal murine breast epithelial cell line NMuMG, and TBX3 protein in turn enhances TGF-β signaling and Wnt signaling, promoting TGF-β/Wnt-induced EMT, creating positive feedback loops. In addition, we have successfully set up an in vivo breast cancer metastasis model in mice. In this proposal, we would investigate, by multi-disciplinary technologies and metastasis mouse model, the interplay and mechanism of TBX3, TGF-β and Wnt in EMT and breast cancer cell invasion and metastasis. The anticipated results would shed light on the molecular mechanisms underlying cell trans-differentiation (EMT) and breast cancer invasion and metastasis. The applicant has published in esteemed interactional journals over 20 articles, which have been cited by over 600 times.