The miR-200b/200a/429 cluster prevents metastasis and induces dormancy in a murine claudin-low mammary tumor cell line

• Published in: Experimental cell research Vol. 369; no. 1; pp. 17 - 26
• Main Authors: Watson, Katrina L., Jones, Robert A., Bruce, Anthony, Moorehead, Roger A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2018
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Cell Line, Tumor; Claudins - genetics; Claudins - metabolism; Dormancy; Down-Regulation - genetics; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor - physiology; LUNGS; MAMMARY GLANDS; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Mammary tumors; METASTASES; Metastasis; Mice; MicroRNA; MicroRNAs - genetics; MicroRNAs - physiology; MiR-200 family; MORPHOLOGY; Multigene Family - physiology; Neoplasm Metastasis; NEOPLASMS; PHENOTYPE; Resting Phase, Cell Cycle - genetics; TUMOR CELLS; Dormancy; MicroRNA; MiR-200 family; Metastasis; Mammary tumors
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2018.04.024

The miR-200 family of microRNAs consisting of miR-141, miR-200a, miR-200b, miR-200c and miR-429 are emerging as important regulators of breast cancer progression. This family of microRNAs maintain mammary epithelial identity and downregulation of miR-200 expression has been associated with epithelial-to-mesenchymal transition in mammary tumors. Therefore, re-expression of one or more miR-200 family members in mammary tumor cells with mesenchymal characteristics may restore an epithelial phenotype including growth and metastasis suppression. To test this hypothesis, the miR-200b/200a/429 cluster was re-expressed in a murine claudin-low cell line, RJ423. Re-expression of the miR-200b/200a/429 cluster in RJ423 cells significantly suppressed the expression of Vim, Snai1, Twist1, Twist2 and Zeb1, reverted RJ423 cells to a more epithelial morphology and significantly inhibited proliferation in vitro. Moreover, the miR-200b/200a/429 cluster prevented lung metastasis in an experimental metastasis model and although tumor initiation was not prevented, re-expression of the miR-200b/200a/429 cluster induced a dormancy-like state where mammary tumors failed to grow beyond ~150 mm3 or grew extremely slowly following intra-mammary injection. These dormant tumors contained elevated levels of collagen and were highly vascularized. Therefore, re-expression of the miR-200b/200a/429 cluster in the claudin-low mammary tumor cell line, RJ423, is sufficient to alter cell morphology, impair metastasis and induce tumor dormancy. [Display omitted] •miR-200 family members regulate mesenchymal gene expression and cell shape.•Expression of miR-200b/200a/429 impairs mammary tumor metastasis.•miR-200b/200a/429 reduces tumor incidence and induces tumor dormancy.