The MiR-186-3p/EREG Axis Orchestrates Tamoxifen Resistance and Aerobic Glycolysis in Breast Cancer Cells

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2019 Apr 11

PMID 30967627

Citations 62

Authors

Mengjia He

Qianni Jin

Cong Chen

Yifeng Liu

Xiangsen Ye

Yulin Jiang

Feihu Ji

Husun Qian

Delu Gan

Shujun Yue

Wei Zhu

Tingmei Chen

Affiliations

Soon will be listed here.

Abstract

Tamoxifen resistance is one of the major challenges for its medical uses in estrogen receptor (ER)-positive breast cancer. Aerobic glycolysis, an anomalous characteristic of glucose metabolism in cancer cells, has been shown to associate with the resistance to chemotherapeutic agents. It remains, however, largely unclear whether and how tamoxifen resistance contributes to aerobic glycolysis in breast cancer. Here, we report that tamoxifen resistance is associated with enhanced glycolysis in ER-positive breast cancer cells. We demonstrate that EREG, an agonist of EGFR, has an important role in enhancing glycolysis via activating EGFR signaling and its downstream glycolytic genes in tamoxifen-resistant breast cancer cells. We further show that EREG is a direct target of miR-186-3p and that downregulation of miR-186-3p by tamoxifen results in EREG upregulation in tamoxifen-resistant breast cancer cells. Importantly, systemic delivery of cholesterol-modified agomiR-186-3p to mice bearing tamoxifen-resistant breast tumors effectively attenuates both tumor growth and [F]-fluoro-deoxyglucose ([F]-FDG) uptake. Together, our results reveal a novel molecular mechanism of resistance to hormone therapies in which the miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in ER-positive breast cancer, suggesting targeting miR-186-3p as a promising strategy for therapeutic intervention in endocrine-resistant breast tumors.

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