最近研究发现ER-α66及其新的异构体ER-α36可在乳腺癌组织中共表达增强Tamoxifen(Tam)抵抗，但其机制不清。由于在单独的ER-α66+或ER-α36+乳腺癌细胞中二者均可通过与HER2的"串话"介导E2非基因组活性并参与Tam抵抗，我们的预实验也显示ER-α66和ER-α36可共定位于乳腺癌细胞浆/膜，并增强E2/Tam介导的MAPK的磷酸化和Tam刺激的细胞增殖，故推测两种受体在乳腺癌细胞中共表达可通过各自介导的非基因组活性增强Tam抵抗。本项目拟采用Western blot、Confocal、CoIP等技术研究二者在乳腺癌中共表达增强Tam抵抗的分子机制，项目的实施可为临床Tam抵抗机制的研究提供一个新的重要机制，确定ER-α36作为ER-α66+乳腺癌Tam治疗重要标志物的作用，并为临床乳腺癌病人基于Tam的联合应用治疗策略的实施提供新的理论依据。

ER-α66 and its variant ER-α36 are recently found to be co-expressed in breast cancer tissues and increase tamoxifen resistance which mechanism is not clear.It has been demonstrated that ER-α66 or ER-α36 alone is invovled in estogen non genomic activity and tamoxifen resistance through cross-talk with HER2 signalling in ER-α66 postive or ER-α36 positive breast cancer cells.Our preliminary data showed that ER-α66 and ER-α36 could be co-located on cytoplasm and membrane of ER-α66 and ER-α36 co-expressing breast cancer cells and enhanced estogen or tamoxifen-mediated phosphorylation of MAPK and AKt and tamoxifen-stimulated cell proliferation. It is deduced that tamoxifen resistance in ER-α66 and ER-α36 co-expressing breast cancer cells can be enhanced through ER-α66 or ER-α36-mediated non genomic activity respectively. The aim of our project is to study the mechanism of enhanced tamoxifen ressitance in ER-α66 and ER-α36 co-expressing breast cancer cells. The study results will provide a new mechanism for study on tamoxifen resistance in clinic, determine the role of ER-α36 as an important marker for tamoxifen therapy in ER-α66 postive breast cancer and provide a new theoretical basis on the strategy of combined therapy based on tamoxifen for breast cancer patients.