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 ShuaiSarah E. Millar, Zhengquan Yu

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

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.

Original languageEnglish
Article number1036
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2017
Externally publishedYes

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