Zhou Jun, Li Wenhui, Ming Jie, Yang Wen, Lu Linlin, Zhang Qiulei, Ruan Shengnan, Huang Tao
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Anticancer Drugs. 2020 Jul;31(6):558-566. doi: 10.1097/CAD.0000000000000943.
Tamoxifen is the main adjuvant endocrine therapeutic agent for patients with estrogen receptor positive breast cancer. However, the resistance to tamoxifen has become a serious clinical challenge and the underlying mechanisms are still poorly understood. TRAF4 is a member of tumor necrosis factor receptor-associated factor family and its role in tamoxifen resistance has not been found. In this study, we aimed to explore the roles of TRAF4 in tamoxifen-treated breast cancer and tamoxifen resistance. Through high-throughput sequencing and differential gene expression analyses, TRAF4 was identified as the research object in this study. The prognosis significance of TRAF4 was studied based on 155 tamoxifen-treated breast cancer patients obtained from Gene Expression Omnibus (GEO) database. We then investigated the TRAF4 expression level in tamoxifen-resistant and the tamoxifen-sensitive breast cancer cell lines with western blot and real-time quantitative PCR. The loss- and gain-of-function assay of TRAF4 in a tamoxifen-resistant cell line was evaluated using colony formation experiments and cell count kit-8 assay. We identified that TRAF4 was overexpressed in tamoxifen-resistant breast cancer cell line and TRAF4 overexpression was associated with worse overall survival (hazard ratio = 2.538, P = 0.017) and cancer-specific survival (hazard ratio = 2.713, P = 0.036) in tamoxifen-treated patients. Knockdown of TRAF4 reversed tamoxifen resistance, while overexpression of TRAF4 increased tamoxifen resistance, which confirmed the role of TRAF4 in tamoxifen resistance. Taken together, our study demonstrated that TRAF4 could be a novel prognostic biomarker for tamoxifen-treated breast cancer patients and a potential therapeutic target for tamoxifen resistance.
他莫昔芬是雌激素受体阳性乳腺癌患者的主要辅助内分泌治疗药物。然而，对他莫昔芬的耐药性已成为一个严峻的临床挑战，其潜在机制仍知之甚少。TRAF4是肿瘤坏死因子受体相关因子家族的成员，尚未发现其在他莫昔芬耐药中的作用。在本研究中，我们旨在探讨TRAF4在他莫昔芬治疗的乳腺癌及他莫昔芬耐药中的作用。通过高通量测序和差异基因表达分析，确定TRAF4为本研究的研究对象。基于从基因表达综合数据库（GEO）获得的155例接受他莫昔芬治疗的乳腺癌患者，研究了TRAF4的预后意义。然后，我们通过蛋白质免疫印迹法和实时定量PCR检测了他莫昔芬耐药和他莫昔芬敏感乳腺癌细胞系中TRAF4的表达水平。使用集落形成实验和细胞计数试剂盒-8检测评估了TRAF4在他莫昔芬耐药细胞系中的功能丧失和功能获得情况。我们发现TRAF4在他莫昔芬耐药的乳腺癌细胞系中过表达，且TRAF4过表达与接受他莫昔芬治疗患者的总生存期较差（风险比=2.538，P=0.017）和癌症特异性生存期较差（风险比=2.713，P=0.036）相关。敲低TRAF4可逆转他莫昔芬耐药，而TRAF4过表达则增加他莫昔芬耐药，这证实了TRAF4在他莫昔芬耐药中的作用。综上所述，我们的研究表明，TRAF4可能是接受他莫昔芬治疗的乳腺癌患者的一种新型预后生物标志物，也是他莫昔芬耐药的潜在治疗靶点。
