MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists

Cong Lv, Fengyin Li, Xiang Li, Yuhua Tian, Yue Zhang, Xiaole Sheng, Yongli Song, Qingyong Meng, Shukai Yuan, Liming Luan, Thomas Andl, Xu Feng, Baowei Jiao, Mingang Xu, Maksim V. Plikus, Xing Dai, Christopher Lengner, Wei Cui, Fazheng Ren, Jianwei Shuai, Sarah E. Millar and Zhengquan Yu ()
Additional contact information
Cong Lv: College of Biological Sciences, China Agricultural University
Fengyin Li: College of Biological Sciences, China Agricultural University
Xiang Li: College of Biological Sciences, China Agricultural University
Yuhua Tian: College of Biological Sciences, China Agricultural University
Yue Zhang: Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine
Xiaole Sheng: College of Biological Sciences, China Agricultural University
Yongli Song: College of Biological Sciences, China Agricultural University
Qingyong Meng: College of Biological Sciences, China Agricultural University
Shukai Yuan: Basic Medical College, Tianjin Medical University
Liming Luan: Vanderbilt University Medical Center
Thomas Andl: Vanderbilt University Medical Center
Xu Feng: State Key Laboratory of Genetic Resources and Evolution of Kunming Institute of Zoology, Chinese Academy of Sciences
Baowei Jiao: State Key Laboratory of Genetic Resources and Evolution of Kunming Institute of Zoology, Chinese Academy of Sciences
Mingang Xu: Perelman School of Medicine, University of Pennsylvania
Maksim V. Plikus: Sue and Bill Gross Stem Cell Research, Center for Complex Biological Systems, University of California, Irvine
Xing Dai: School of Medicine, University of California
Christopher Lengner: School of Veterinary Medicine, University of Pennsylvania
Wei Cui: College of Biological Sciences, China Agricultural University
Fazheng Ren: College of Biological Sciences, China Agricultural University
Jianwei Shuai: Innovation Center for Cell Signaling Network, Xiamen University
Sarah E. Millar: Perelman School of Medicine, University of Pennsylvania
Zhengquan Yu: College of Biological Sciences, China Agricultural University

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-κB signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGFβ and Wnt/β-catenin. Particularly, it activates Wnt/β-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.

Date: 2017
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DOI: 10.1038/s41467-017-01059-5

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