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

Int J Oncol. 2018 Oct;53(4):1601-1612. doi: 10.3892/ijo.2018.4492. Epub 2018 Jul 19.

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.

MeSH terms

  • Adult
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • E2F7 Transcription Factor / genetics*
  • E2F7 Transcription Factor / metabolism
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Small Interfering / metabolism
  • Receptors, Estrogen / metabolism
  • Tamoxifen / pharmacology*
  • Tamoxifen / therapeutic use
  • Up-Regulation

Substances

  • Antineoplastic Agents, Hormonal
  • E2F7 Transcription Factor
  • E2F7 protein, human
  • MAS1 protein, human
  • MIRN26A microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Tamoxifen