细胞极性蛋白CRB3缺失在乳腺癌发生发展中的作用机制研究

上皮细胞极性缺失是癌细胞区别于正常上皮细胞的特征性改变，对极性紊乱的研究是目前癌症研究的前沿与热点领域之一。近年来研究表明，CRB3是维持上皮细胞顶底极性的决定性蛋白，CRB3缺失与癌症的发生发展关系密切，然而很多关键机制尚不清楚。我们的前期结果显示，CRB3与Hippo 信号通路关系密切，其缺失可影响乳腺癌细胞EMT进程及乳腺癌干细胞样特征，在乳腺癌细胞中外源性表达CRB3可诱导癌细胞凋亡。基于此，我们设想：CRB3缺失是乳腺上皮细胞极性紊乱并发生恶性转化的重要因素；CRB3缺失可导致乳腺癌细胞发生EMT,并与乳腺癌干细胞样表征相关；CRB3可能在肿瘤治疗中有重要作用。我们拟以乳腺癌为研究对象，利用细胞分子生物学技术，通过体内外实验对CRB3在乳腺癌发生发展中的作用机制进行深入探究。该项目的完成，将可阐明CRB3丧失在乳腺癌恶性进程中的全新机制，并为筛选抗癌新靶点提供理论依据。

Loss of cell polarity is one of the traits of cancer cells, which makes them different from epithelial cells. Studies on the mechanism underlying loss of cell polarity in cancer development has become one of the hottest fields in cancer research. Recent studies have shown that loss of CRB3, an epithelial cell apical-basal polarity determinant, plays crucial roles in cancer tumorigenesis and development. However, the mechanism underlying loss of CRB3 in malignant progression of breast cancer is still unclear. Our preliminary data have shown that CRB3 expression is significantly decreased or lost in breast cancer cells and clinical breast cancer tissues, and that loss of CRB3 is closely related to cancer malignant progression. Based on previous literature reports and our preliminary data, we hypothesize that loss of CRB3 may lead to disorder of mammary gland cell polarity, be closely related to malignant progression of breast cancer, and consequently, give rise to epithelial-mesenchymal transition (EMT) of breast cancer cells and breast cancer stem cell-like traits. We also hypothesize that restore of CRB3 may give rise to apoptosis in breast cancer cells and that CRB3 may be a novel target for cancer therapy. We plan to conduct research on the effects of loss of CRB3 on malignant progression of human breast cancer by using cellular and molecular biological techniques in vitro and in vivo, and to clarify a novel mechanism by which CRB3 affects the malignant progression of breast cancer.This project is expected to provide a theoretical basis for breast cancer malignant progression and for screening for a novel anti-cancer target.