Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis

• Published in: Oncogene Vol. 38; no. 3; pp. 445 - 453
• Main Authors: Patel, Y., Soni, M., Awgulewitsch, A., Kern, M. J., Liu, S., Shah, N., Singh, U. P., Chen, H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2019; Nature Publishing Group
• Subjects: 13/100; 13/31; 631/532/71; 631/67/1347; 631/67/70; 64/110; 64/60; 82/51; Animal genetic engineering; Animal models; Animals; Antigens, CD - analysis; Apoptosis; Breast cancer; Brief Communication; Cancer metastasis; Carcinogenesis; Cell Biology; Cell Differentiation; Cell Transformation, Neoplastic - genetics; Cellular signal transduction; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial cells; Epithelial Cells - metabolism; ErbB-2 protein; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic engineering; Genetic transformation; Health aspects; Human Genetics; Internal Medicine; Lung Neoplasms - secondary; Mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mammary Tumor Virus, Mouse - genetics; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - physiology; miRNA; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncology; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - metabolism; Pregnancy; Progenitor cells; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - physiology; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - metabolism; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; RNA, Neoplasm - physiology; Signal transduction; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Transgenic mice; Tumor Stem Cell Assay; Tumor suppressor genes; Tumorigenesis; Tumors; Up-Regulation; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0439-1

Although it has been demonstrated that transformed progenitor cell population can contribute to tumor initiation, factors contributing to this malignant transformation are poorly known. Using in vitro and xenograft-based models, previous studies demonstrated that miR-489 acts as a tumor suppressor miRNA by targeting various oncogenic pathways. It has been demonstrated that miR-489 directly targets HER2 and inhibits the HER2 signaling pathway; however, its role in mammary gland development and HER2-induced tumor initiation hasn’t been studied. To dissect the role of miR-489, we sorted different populations of mammary epithelial cells and determined that miR-489 was highly expressed in mammary stem cells. MMTV-miR-489 mice that overexpressed miR-489 in mammary epithelial cells were developed and these mice exhibited an inhibition of mammary gland development in early ages with a specific impact on highly proliferative cells. Double transgenic MMTV-Her2 - miR489 mice were then generated to observe how miR-489 overexpression affects HER2-induced tumorigenesis. miR-489 overexpression delayed HER2-induced tumor initiation significantly. Moreover, miR-489 overexpression inhibited tumor growth and lung metastasis. miR-489 overexpression reduced mammary progenitor cell population significantly in preneoplastic mammary glands of MMTV-Her2 mice which showed a putative transformed population in HER2-induced tumorigenesis. The miR-489 overexpression reduced CD49f hi CD61 hi populations in tumors that have stem-like properties, and miR-489 overexpression altered the HER2 signaling pathway in mammary tumors. Altogether, these data indicate that the inhibition of HER2-induced tumorigenesis by miR-489 overexpression was due to altering progenitor cell populations while decreasing tumor growth and metastasis via influencing tumor promoting genes DEK and SHP2.