A miR-26a/E2F7 feedback loop contributes to tamoxifen resistance in ER-positive breast cancer

Liu,Jian; Li,Xiang; Wang,Meng; Xiao,Guodong; Yang,Ganghua; Wang,Huangzhen; Li,Yanbo; Sun,Xin; Qin,Sida; Du,Ning; Ren,Hong; Pang,Yamei

doi:10.3892/ijo.2018.4492

A miR-26a/E2F7 feedback loop contributes to tamoxifen resistance in ER-positive breast cancer

Authors:
- Jian Liu
- Xiang Li
- Meng Wang
- Guodong Xiao
- Ganghua Yang
- Huangzhen Wang
- Yanbo Li
- Xin Sun
- Sida Qin
- Ning Du
- Hong Ren
- Yamei Pang
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Affiliations: The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Surgical Oncology, Baoji Central Hospital, Baoji, Shaanxi 721008, P.R. China, Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: July 19, 2018 https://doi.org/10.3892/ijo.2018.4492
Pages: 1601-1612

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Abstract

Tamoxifen (TAM) resistance is a substantial challenge in the treatment of estrogen receptor (ER)-positive breast cancer. Previous studies have revealed an important role of microRNA (miRNA/miR)-26a in TAM resistance in breast cancer. However, the mechanism underlying the regulatory effects of miR-26a on TAM resistance remains to be elucidated. The expression levels of miR-26a in ER-positive breast cancer were detected by reverse transcription-quantitative polymerase chain reaction. E2F transcription factor 7 (E2F7) and MYC proto-oncogene, bHLH transcription factor (MYC) levels were detected by western blotting. The present study demonstrated that miR-26a expression was reduced in ER-positive breast cancer compared with in normal breast tissues, whereas E2F7 expression was significantly elevated. Furthermore, an inverse correlation between miR-26a and E2F7 expression was detected in ER-positive breast cancer. The results indicated that miR-26a directly inhibited E2F7 expression through translational inhibition and indirectly inhibited MYC expression partly via E2F7 repression. E2F7, in turn, decreased miR-26a expression via MYC-induced transcriptional inhibition of miRNAs. Furthermore, transfection with miR-26a mimics increased the expression of its host genes (CTD small phosphatase like and CTD small phosphatase 2), whereas ectopic E2F7 expression abrogated the effects of miR-26a. These findings indicated that miR-26a and E2F7 may form a double-negative feedback loop, resulting in downregulation of miR-26a and upregulation of E2F7 in ER-positive breast cancer. Both miR-26a knockdown and E2F7 overexpression conferred resistance to TAM in MCF-7 cells. Conversely, miR-26a overexpression and E2F7 silencing resensitized MCF-7 resistant cells to TAM. These findings revealed that a feedback loop between miR-26a and E2F7 may promote TAM resistance in ER-positive breast cancer.

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