Journal Article

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

Cui, Wei, Tian, Yuhua, Yuan, Shukai, Jiao, Baowei, Andl, Thomas, Dai, Xing, Sheng, Xiaole, Lengner, Christopher, Millar, Sarah E., Li, Fengyin, Meng, Qingyong, Lv, Cong, Zhang, Yue, Feng, Xu, Xu, Mingang, Song, Yongli, Luan, Liming, Li, Xiang, Shuai, Jianwei, Ren, Fazheng, Plikus, Maksim V., Yu, Zhengquan

2017

Overview

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. MicroRNAs play an important role in stem cell fate and tumorigenesis. In this work, the authors show that miR-31 controls mammary stem cell self-renewal and tumorigenesis by simultaneously activating Wnt/β-catenin and repressing TGFβ signaling pathways.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/136/532/2436 / 631/67/1347 / Animals / beta Catenin - metabolism / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - physiopathology / Cancer / Cell fate / Cell Line, Tumor / Cell Proliferation / Cell Self Renewal / Dkk1 protein / Down-Regulation / Female / Gene Expression Regulation, Neoplastic / Gene regulation / Humanities and Social Sciences / Humans / Lungs / Mammary gland / Mammary Glands, Human - cytology / Mammary Glands, Human - metabolism / Metastases / Mice / Mice, Inbred C57BL / Mice, Transgenic / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / multidisciplinary / Neoplastic Stem Cells - cytology / Neoplastic Stem Cells - metabolism / NF-kappa B - genetics / NF-kappa B - metabolism / NF-κB protein / Post-transcription / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Signal transduction / Stat5 protein / Stem cells / Stem Cells - cytology / Stem Cells - metabolism / Transcription / Tumorigenesis / Tumors / Wnt protein / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt Signaling Pathway / β-Catenin