Wnt pathway targeting reduces triple‐negative breast cancer aggressiveness through miRNA regulation in vitro and in vivo

• Published in: Journal of cellular physiology 2019-10, Vol.234 (10), p.18317-18328
• Main Authors: Mohammadi‐Yeganeh, Samira, Hosseini, Vahedeh, Paryan, Mahdi
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Animals; Bioinformatics; Breast cancer; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cell survival; Computational Biology - methods; Computer applications; CTNNB1; c‐MYC; Diagnostic systems; Epidermal growth factor; Estrogen receptors; Estrogens; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genes; Growth factors; Humans; Invasiveness; Kinases; Lung cancer; MCF-7 Cells; Mice; Mice, Inbred C57BL; Mice, Nude; MicroRNAs - genetics; miRNA; miR‐381; Myc protein; Polymerase chain reaction; Progesterone; Restoration; RhoA; RhoA protein; ROCK1; Signal transduction; Signaling; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; triple‐negative breast cancer; Wnt protein; Wnt Signaling Pathway - genetics
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28465

Triple‐negative breast cancer, devoid of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER‐2) expression, is deprived of commonly used targeted therapies. MicroRNAs (miRNAs) are undergoing a revolution in terms of potentially diagnostic or therapeutic elements. Combining computational approaches, we enriched miRNA binding motifs of Wnt pathway‐associated upregulated genes. Our in‐depth bioinformatics, in vitro and in vivo analyses indicated that miR‐381 targets main genes of the Wnt signaling pathway including CTNNB1, RhoA, ROCK1, and c‐MYC genes. The expression level of miR‐381 and target genes was assessed by quantitative real‐time polymerase chain reaction (RT‐qPCR) in MCF‐7, MDA‐MB‐231, and MCF‐10A as well as 20 breast cancer samples and normal tissues. Luciferase reporter assay was performed. Lentiviral particles containing miR‐381 were used to evaluate the effect of miR‐381 restoration on cell proliferation, migration, and invasion of the invasive triple‐negative MDA‐MB‐231 cell line and also in a mouse model of breast cancer. The expression of miR‐381 was lower than that of normal cells, especially in TNBC cell line and breast tissues. Luciferase assay results confirmed that miR‐381 targets all the predicted 3′‐untranslated regions (3′‐UTRs). Upon miR‐381 overexpression, the expression of target genes declined, and the migration and invasion potential of miR‐381‐receiving MDA‐MB‐231 cells decreased. In a mouse model of triple‐negative breast cancer, miR‐381 re‐expression inhibited the invasion of cancer cells to lung and liver and prolonged the survival time of cancer cell‐bearing mice. Therefore, miR‐381 is a regulator of Wnt signaling and its re‐expression provides a potentially effective strategy for inhibition of TNBC. Combining computational approaches, we enriched miRNA binding motifs of the Wnt pathway associated with upregulated genes that miR‐381 targets main genes of the Wnt signaling pathway including CTNNB1, RhoA, ROCK1, and c‐MYC genes.In a mouse model of TNBC, miR‐381 re‐expression inhibited the invasion of cancer cells to lung and liver and prolonged the survival time of cancer cell‐bearing mice.