E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter
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Junjun Chu1,2,3, Yinghua Zhu1,2, Yujie Liu1,2, Lijuan Sun1,2,3, Xiaobin Lv1,2, Yanqin Wu1,2, Pengnan Hu1,2,3, Fengxi Su1,2, Chang Gong1,2, Erwei Song1,2,3, Bodu Liu1,2,3, Qiang Liu1,2
1Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
2Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
3Key Laboratory of Gene Engineering of Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
Qiang Liu, e-mail: firstname.lastname@example.org
Bodu Liu, e-mail: email@example.com
Keywords: breast cancer, tamoxifen resistance, E2F7, miR-15a/16, prognostic marker
Received: March 18, 2015 Accepted: August 31, 2015 Published: September 12, 2015
About 50–70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.
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