Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 21; pp. 6424 - 6435
• Main Authors: Kim, Jongchan, Siverly, Ashley N, Chen, Dahu, Wang, Min, Yuan, Yuan, Wang, Yumeng, Lee, Hyemin, Zhang, Jinsong, Muller, William J, Liang, Han, Gan, Boyi, Yang, Xianbin, Sun, Yutong, You, M James, Ma, Li
• Format: Journal Article
• Language: English
• Published: United States 01.11.2016
• Subjects: Animals; Carcinogenesis; Dyrk Kinases; Epithelial-Mesenchymal Transition; Homeodomain Proteins - genetics; Mammary Neoplasms, Experimental - etiology; Mammary Neoplasms, Experimental - pathology; Mammary Neoplasms, Experimental - prevention & control; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred C57BL; MicroRNAs - physiology; Neoplasm Metastasis; Oncogenes; Protein Serine-Threonine Kinases - genetics; Protein-Tyrosine Kinases - genetics; PTEN Phosphohydrolase - genetics; T-Box Domain Proteins - genetics; T-Box Domain Proteins - physiology; Transcription Factors - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-1571

The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b-deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer. Among the target genes of miR-10b, the tumor suppressor genes Tbx5 and Pten and the metastasis suppressor gene Hoxd10 are significantly upregulated by miR-10b deletion. Mechanistically, miR-10b promotes breast cancer cell proliferation, migration, and invasion through inhibition of the expression of the transcription factor TBX5, leading to repression of the tumor suppressor genes DYRK1A and PTEN In clinical specimens of breast cancer, the expression of TBX5, HOXD10, and DYRK1A correlates with relapse-free survival and overall survival outcomes in patients. Our results establish miR-10b as an oncomiR that drives metastasis, termed a metastamiR, and define the set of critical tumor suppressor mechanisms it overcomes to drive breast cancer progression. Cancer Res; 76(21); 6424-35. ©2016 AACR.