雌激素（E2）是女性体内的主要性激素，在女性生殖系统和乳腺生长发育及生理功能调节中发挥重要作用，然而在异常情况下E2则是促进乳腺癌恶性进展的重要因素。已发现E2可通过G蛋白偶联雌激素受体（GPER）激活乳腺癌细胞钙蛋白酶（CANP）并影响其生物学行为，但其下游信号通路尚未完全阐明。为此，我们尝试提出“E2/GPER通过Src-CANP2-纤连蛋白（FN）-Src反馈环路调控三阴乳腺癌（TNBC）细胞上皮-间质转化（EMT）表型的变化并促进肿瘤转移”的科学假设。本项目拟采用现代生物学研究手段，在细胞和分子水平对上述科学假设进行重点研究，并通过建立小鼠肿瘤转移模型，在整体水平验证上述离体实验结果。通过本项目研究，实现深入认识和阐明E2/GPER信号通路及其生物学作用的目标，并力图发现GPER通路中调控TNBC转移的关键分子，为探寻基于GPER信号通路的TNBC治疗新策略提供实验依据。

Estrogen (17β-Estradiol, E2) is the primary sex hormone in women and plays a key role in regulation of the growth/development and physiological functions of the female reproductive system and breasts. Under abnormal conditions, however, it may exert important effects on the malignant progression of breast cancer. It has been found that G protein coupled estrogen receptor (GPER) could activate calpain in breast cancer cells, yet its downstream signal pathway is not fully understood. Here we try to propose a hypothesis that E2/GPER may regulate the alteration of epithelial-mesenchymal transition (EMT) phenotype via a Src-calpain2-fibronectin-Src positive feedback that promotes metastasis of triple negative breast cancer (TNBC). We’ll use modern biological methodologies to investigate the above proposed hypothesis at cellular and molecular levels. Briefly, we’ll assess the effect of E2/GPER on the alteration of EMT phenotype and a role of Src-calpain2-FN-Src positive feedback in the E2/GPER’s effect. Furthermore, xenograft in Scid mice will be used to validate the results obtained from the above in vitro studies. The goal of the proposed research program is to better understand and clarify the E2/GPER signaling and its biological role, and hopefully to find a key molecule(s) involved in controlling metastasis of TNBC，thus providing experimental evidence for a novel therapy strategy for TNBC.