Zeng Yuanying, Xu Xin, Wang Siyu, Zhang Zubin, Liu Yan, Han Kunkun, Cao Biyin, Mao Xinliang
Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho- Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
Department of Oncology, Suzhou Municipal Hospital East Campus, Suzhou, 215100, P.R. China.
Oncotarget. 2017 Mar 21;8(12):20103-20112. doi: 10.18632/oncotarget.15384.
Ring finger protein 6 (RNF6) is a key oncogene in both prostate cancer and leukemia, but its role is elusive in breast cancer. In the present study, we found that RNF6 was overexpressed in more than 70% of breast cancer tissues and it was associated with overall survival. RNF6 increased breast cancer cell proliferation, migration and reduced cell sensitivity to doxorubicin. Further studies showed that RNF6 was closely associated with increased expression of estrogen receptor, a critical factor in the development of breast cancers. RNF6 was found to induce ERα expression and increased its stability. In doxorubicin-resistant breast cancer cells, RNF6 was found to be elevated in association with increased ERα and anti-apoptotic Bcl-xL, but not pro-apoptotic Bim-1. In consistence with this finding, overexpression of ERα led to increased Bcl-xL but had no effects on Bim-1. Therefore, this study demonstrated that there exists an RNF6/ERα/Bcl-xL axle in breast cancer which promotes cancer cell proliferation and survival. Targeting the RNF6/ERα/Bcl-xL axle could be a promising strategy in the treatment of breast cancer.
无名指蛋白6（RNF6）在前列腺癌和白血病中都是关键致癌基因，但其在乳腺癌中的作用尚不清楚。在本研究中，我们发现RNF6在70%以上的乳腺癌组织中过表达，且与总生存期相关。RNF6可促进乳腺癌细胞增殖、迁移，并降低细胞对多柔比星的敏感性。进一步研究表明，RNF6与雌激素受体表达增加密切相关，雌激素受体是乳腺癌发生发展的关键因素。研究发现，RNF6可诱导雌激素受体α（ERα）表达并增加其稳定性。在多柔比星耐药的乳腺癌细胞中，发现RNF6升高与ERα及抗凋亡蛋白Bcl-xL增加有关，但与促凋亡蛋白Bim-1无关。与此发现一致，ERα过表达导致Bcl-xL增加，但对Bim-1无影响。因此，本研究表明乳腺癌中存在RNF6/ERα/Bcl-xL轴，该轴促进癌细胞增殖和存活。靶向RNF6/ERα/Bcl-xL轴可能是治疗乳腺癌的一种有前景的策略。
