MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ

Mingrong Lü; Keshuo Ding; Guofeng Zhang; Mianmian Yin; Guidong Yao; Hui Tian; Jie Lian; Lin Liu; Meng Liang; Tao Zhu; Fei Sun

doi:10.1038/srep08735

MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ

Sci Rep. 2015 Mar 4:5:8735. doi: 10.1038/srep08735.

Authors

Mingrong Lü¹, Keshuo Ding², Guofeng Zhang³, Mianmian Yin¹, Guidong Yao⁴, Hui Tian¹, Jie Lian¹, Lin Liu¹, Meng Liang¹, Tao Zhu¹, Fei Sun¹

Affiliations

¹ 1] Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China [2] Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, People's Republic of China.
² 1] Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China [2] Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, People's Republic of China [3] Department of Pathology, Anhui Medical University, Hefei, Anhui, People's Republic of China.
³ Department of General Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, People's Republic of China.
⁴ Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China.

Abstract

Tamoxifen represents a major adjuvant therapy to those patients with estrogen receptor-alpha positive breast cancer. However, tamoxifen resistance occurs quite often, either de novo or acquired during treatment. To investigate the role of miR-320a in the development of resistance to tamoxifen, we established tamoxifen-resistant (TamR) models by continually exposing MCF-7 or T47D breast cancer cells to tamoxifen, and identified microRNA(miRNA)-320a as a down-regulated miRNA in tamoxifen resistant cells. Re-expression of miR-320a was sufficient to sensitize TamR cells to tamoxifen by targeting cAMP-regulated phosphoprotein (ARPP-19) and estrogen-related receptor gamma (ERRγ) as well as their downstream effectors, c-Myc and Cyclin D1. Furthermore, progesterone (P4) promoted the expression of miR-320a by repressing c-Myc expression, while estrogen (E2) exerted the opposite effect. These results suggest the potential therapeutic approach for tamoxifen-resistant breast cancer by restorating miR-320a expression or depleting ARPP-19/ERRγ expression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Hormonal / pharmacology
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Drug Resistance, Neoplasm / genetics*
Estrogens / pharmacology
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Humans
MCF-7 Cells
Mice, Nude
MicroRNAs / genetics*
Phosphoproteins / genetics*
Phosphoproteins / metabolism
Progesterone / pharmacology
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Estrogen / genetics*
Receptors, Estrogen / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tamoxifen / pharmacology*
Xenograft Model Antitumor Assays / methods

Substances

Antineoplastic Agents, Hormonal
ESRRG protein, human
Estrogens
MIRN320 microRNA, human
MicroRNAs
Phosphoproteins
Proto-Oncogene Proteins c-myc
Receptors, Estrogen
cyclic AMP-regulated phosphoprotein 19
Tamoxifen
Progesterone