BARD1过表达促进了乳腺癌他莫昔芬耐药的发生

Tamoxifen is a central component of the endocrine therapy in ERα positive breast cancer patients. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. In this project, we established MCF-7 tamoxifen resistant cell model by long term exposure to tamoxifen, and analyzed the gene expression differences by using gene expression microarray. The high expressed gene in tamoxifen resistant cell were screen out by oncomine platform and the results indicate that high expressed BARD1 is associate with poor prognosis. we evidenced BARD1 play important role in tamoxifen resistance in vitro by changing the expression of BARD1. However what is the mechanism of BARD1 in regulating breast cancer tamoxifen resistance? The pre experiment indicate that over expressed BARD1 incresed the transcription activity of ERα. Thus, we propose that BARD1 promote breast cancer tamoxifen resistance by promoting the transcription activity of ERα. This project aims to further predicted the binding sites of BARD1 and ERα by bioinformatics, obtain molecular evidence of BARD1 regulating of ER transcriptional activity by point mutation, EMSA, confocal laser scanning and other methods, finally provide more scientific basis to establish BARD1 as a new target of endocrine therapy for breast cancer.

他莫昔芬耐药是乳腺癌内分泌治疗亟待解决的科学难题,我们通过体外诱导建立了乳腺癌他莫昔芬耐药模型,并对这一模型进行基因表达谱分析.利用ONCOMINE癌症数据分析平台, 对耐药株中高表达的基因进行临床预后分析筛选出具有临床研究价值的基因BARD1. 那么,BARD1是否在乳腺癌他莫昔芬耐药中发挥了作用?我们通过改变BARD1的表达, 发现BARD1在他莫昔芬耐药中发挥了重要作用. BARD1调控乳腺癌他莫昔芬耐药的机制又是什么? 预实验结果显示,BARD1的过表达促进了ERα的转录激活. 由此, 我们提出过表达的BARD1通过促进ERα的转录激活促进了乳腺癌他莫昔芬耐药的发生. 本项目拟进一步采用生物信息学技术预测BARD1与ERα结合位点，利用点突变,EMSA,激光共聚焦等方法获得BARD1调控ERα转录活性的分子生物学证据,为确立BARD1作为乳腺癌内分泌治疗新靶点提供更充分的科学依据.