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

• Published in: Nature communications Vol. 8; no. 1; pp. 1036 - 18
• Main Authors: Lv, Cong, Li, Fengyin, Li, Xiang, Tian, Yuhua, Zhang, Yue, Sheng, Xiaole, Song, Yongli, Meng, Qingyong, Yuan, Shukai, Luan, Liming, Andl, Thomas, Feng, Xu, Jiao, Baowei, Xu, Mingang, Plikus, Maksim V., Dai, Xing, Lengner, Christopher, Cui, Wei, Ren, Fazheng, Shuai, Jianwei, Millar, Sarah E., Yu, Zhengquan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-10-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01059-5

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.