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

• DOI: 10.1038/s41467-017-01059-5
• Publication Date: 2017-10-13T13:21:38Z
• Authors: 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; Zhengquan Yu
• Keywords: METASTASIS SUPPRESSOR; NF-KAPPA-B; TO-MESENCHYMAL TRANSITION; INVASION; Inbred C57BL; Transgenic; Mice; Stem Cell Research - Nonembryonic - Human; 2.1 Biological and endogenous factors; Aetiology; Cell Self Renewal; Wnt Signaling Pathway; beta Catenin; Cancer; GENE-EXPRESSION; Tumor; Stem Cells; Q; NF-kappa B; EPITHELIAL-CELLS; Biological Sciences; Mammary Glands; CANCER; 3. Good health; Multidisciplinary Sciences; Gene Expression Regulation, Neoplastic; DIFFERENTIATION; Neoplastic Stem Cells; Science & Technology - Other Topics; Stem Cell Research - Nonembryonic - Non-Human; Female; Biotechnology; Human; Science; 610; Down-Regulation; Breast Neoplasms; Mice, Transgenic; Article; Cell Line; Medicinal and Biomolecular Chemistry; Cell Line, Tumor; Breast Cancer; GLAND DEVELOPMENT; Genetics; Animals; Humans; Mammary Glands, Human; Cell Proliferation; P-CADHERIN; Neoplastic; Science & Technology; Stem Cell Research; Mice, Inbred C57BL; Wnt Proteins; MicroRNAs; Gene Expression Regulation; Chemical Sciences; Biochemistry and Cell Biology

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