PRMT2对乳腺癌细胞增殖和耐药的影响及机制研究

Breast cancer is one of the most common malignancies in female, and E2/ER-α signaling plays an important role in the initiation and progression of breast cancer. The role of ER-α subtype and its co-regulators in the initiation and drug resistance occurrence of breast cancer remains to be further elucidated. In our previous work, PRMT2, a co-regulator of ER-α, were confirmed to interact with ER-α 36 in breast cancer cells,and PRMT2 was also observed to have the ability to suppress the proliferation of breast cancer cells. Here, we propose that PRMT2 is implicated with ER-α 36 mediated non genomic effect, affecting the proliferation and drug resistance of breast cancer cells. In this project we would focus on: to unravel the relationship between PRMT2 and ER-a 36 in the regulation of proliferation and drug resistance occurrence of breast cancer cells; to understand the roles of PRMT2 in the regulation of proliferation and drug resistance occurrence of breast cancer cells; to reveal the clinical importance of PRMT2 in the initiation and drug resistance of breast cancer. The completion of the project would be meaningful for understanding the roles of PRMT2 in breast cancer progression and for the developing new endocrine therapy strategy for breast cancer patients with drug resistance.

乳腺癌是女性最常见恶性肿瘤之一， E2/ER-α在乳腺癌发生发展中发挥重要作用, 而不同亚型ER-α及其功能性共调节因子在乳腺癌发生及耐药形成中的作用及机制尚不清楚。课题组前期工作首次证实了作为ER-α共调节因子的PRMT2与ER-α36在乳腺癌细胞中存在相互作用，PRMT2能抑制乳腺癌细胞的增殖。基于此，本课题提出PRMT2可能通过与ER-α36的相互作用参与 ER-α36介导的非基因组效应，影响乳腺癌细胞的增殖和耐药的形成。课题拟明确在乳腺癌细胞增殖调控和耐药形成过程中PRMT2与ER-α 36之间的关系；阐明PRMT2在乳腺癌细胞增殖和耐药形成中的作用及分子机制；探讨PRMT2在乳腺癌发生和耐药中的临床意义。本课题的完成对于明确PRMT2在乳腺癌发生中的作用具有重要意义，可为耐药性乳腺癌的内分泌治疗提供新的思路。

本项目证实了在乳腺癌发生过程中PRMT2与ER-α36发生相互作用，明确了在乳腺癌细胞增殖调控和耐药形成过程中PRMT2与ER-α36之间的关系，发现MDA-MA-231细胞对他莫昔芬（TAM）耐药与PRMT2的下调和ER-α36表达增加有关，且可能通过调控ER-ɑ36介导的非基因组效应（PI3K-AKT和MAPK/ERK信号通路）参与乳腺癌细胞耐药的形成；通过荧光免疫分析发现ER-α36和PRMT2的荧光信号重叠，表明在乳腺癌细胞内ERα-36与PRMT2存在共定位现象；Co-IP和GST-pull down实验提示ER-α36和PRMT2存在直接的相互作用；抑制内源性PRMT2的表达可促进Cyclin D1显著增加，反之，高表达PRMT2则抑制了Cyclin D1的表达，间接说明PRMT2的高表达可以介导乳腺癌细胞的增殖和对TAM的反应。以上结果阐明了PRMT2影响乳腺癌细胞增殖调控和耐药形成的分子机制，证实了PRMT2能通过与ER-α36相互作用或者抑制ER-α36的表达从而抑制ER-α36介导的非基因组效应，继而逆转乳腺癌细胞对他莫昔芬的耐药，因此，PRMT2可能成为一个克服他莫昔芬耐药的新靶点，也是一个良好的乳腺癌治疗的预后指标。项目从细胞、分子和临床多层面揭示了PRMT2在乳腺癌增殖和耐药过程中的作用及其机制，明确了PRMT2在乳腺癌发展中存在的复杂作用和功能，为进一步研究乳腺癌增殖和耐药中所涉及的信号网络提供了实验基础和理论依据。