RNF34通过泛素化ERα参与乳腺癌内分泌耐药的分子机制研究

The expression level and transcrpitonal activity of ERα are important risk factors for breast cancer development and tamoxifen resistance. Although ubiquitination of ERα is of vital importance to cancer development and especially to endocrine resistance, the contributions of E3 ligases are still not fully understood. By screening in RNA interference pool of E3 ligase, we found RNF34 increases ERα transcriptional activity. Specially, RNF34 interacts with ERα and upregulates its ubiquitination level through its E3 ligase activity. Furthermore, analysis of database GSE15852 revealed that RNF34 expression in tumor samples was much higher compared to their matched adjacent tissues. Taken together, we would like to explore the interaction of RNF34 with ERα and their biological significance, and elucidate the importance of RNF34 in tumorigenesis, endocrine resistance and potential usefulness as a diagnostic and therapeutic target for breast cancer.

ERα表达及其转录活性失调与乳腺癌密切相关。虽然已有ERα的泛素化修饰参与ERα调控的报道，但关于E3泛素化连接酶调控ERα参与乳腺癌发生发展及预后的研究尚未深入开展。我们前期通过E3连接酶的小干扰RNA文库，筛选到一个可能增强ERα转录活性的E3连接酶RNF34。初步研究发现RNF34能够与ERα发生相互作用，并且降低ERα的稳定性；体内泛素化分析发现RNF34能够显著增强ERα泛素化；公共数据集分析发现RNF34 mRNA在乳腺癌中高表达。本课题拟进一步研究RNF34调控ERα稳定性及转录活性的生理学意义及分子机制；探讨RNF34调控ERα对乳腺癌的发生、发展及预后的影响，并通过临床乳腺癌大样本进行综合评估。该研究的开展，有助于阐明ERα泛素化修饰与其稳定性的关系，明确ERα泛素化调控其转录活性的分子机制，最终为临床实践提供乳腺癌潜在的诊断或药物靶标。

雌激素受体α(ERα)在乳腺癌及内分泌治疗中扮演着关键角色。虽然已有ERα的泛素化修饰参与ERα调控的报道，但关于E3泛素化连接酶调控ERα参与乳腺癌发生发展及预后的研究尚未深入开展。在本研究中，我们发现RNF34是ERα的E3连接酶，可通过泛素化降低其稳定性，并增强ERα的转录活性。ERα在lys-180位点的泛素化使其转录激活。RNF34缺乏导致乳腺癌细胞对他莫昔芬治疗更敏感，RNF34通过调控ERα的泛素化促进乳腺癌细胞对他莫昔芬治疗耐药。RNF34在乳腺癌中的表达与患者预后相关，高表达RNF34的乳腺癌患者预后较差。综上，RNF34可泛素化ERα，降低其稳定性，导致乳腺癌他莫昔芬治疗耐药。