EGFR和TGFβ信号通路与肿瘤发生发展关系密切。EGFR通路的活化促进肿瘤进展，而TGFβ在肿瘤发生发展过程中发挥双向调节的作用。这两个通路间存在交互作用，且这种交互作用能够促进肿瘤进展和靶向药物的耐药，但其分子机制尚不明确。前期研究发现TGFβ促进乳腺癌细胞迁移侵袭的同时，伴随着EGFR表达增加和下游通路的激活；而降低EGFR的表达则抑制TGFβ的作用。进一步发现EGFR的启动子区存在转录因子Smad3和SP1的结合位点，且TGFβ能够促进SP1与EGFR启动子区的结合，并增强启动子的活性，初步证实TGFβ可能反式激活EGFR信号通路。本研究拟采用染色质免疫共沉淀、荧光素酶报告基因实验、免疫荧光、Western blot、RNA干扰和乳腺癌转移小鼠模型等多种实验方法，阐明TGFβ反式激活EGFR信号通路的分子机制，明确EGFR在介导TGFβ激活经典Smad和非Smad信号通路中的作用。

EGFR and TGFβ signal pathway are critical for cancer initiation and progression. Activation of EGFR signaling predominantly promotes tumorigenesis and development, whereas TGFβ acts a potent tumor suppressor and tumor enhancer in a context-dependent manner. Cross-talk between EGFR and TGFβ signaling pathway was observed in many types of tumors, and was correlated with cancer progression and resistance to EGFR-targeted drugs. However, the detailed mechanism remains unclear. Our previous study showed that TGFβ promotes migration and invasion of breast cancer cells along with elevated expression of EGFR protein and activation of EGFR downstream signaling, and knockdown of EGFR inhibits this promoting effect of TGFβ. In addition, two Smad3 and multiple SP1 binding sites were identified in the EGFR promoter region. We further found that TGFβ induced a significant enhancement of the binding capacity of SP1 to EGFR promoter. Moreover, the promoter activity of EGFR was also enhanced after TGFβ stimulation. These data suggest that TGFβ could transactivate EGFR signaling in breast cancer cells. In this study, we plan to use chromatin immunoprecipitation assay, luciferase reporter assay, immunofluorescence, Western blot, RNA interference methods and in vivo SCID mouse model to investigate the molecular mechanism through which TGFβ transactivates EGFR signaling, and to clarify the detailed role of EGFR in TGFβ-induced activation of canonical Smad and Non-Smad signaling.