Abstract
MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of β-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.
Highlights
BC will be diagnosed and 40 610 cancer deaths will be occurred in BC in 2017.2 The main carcinogenic factors, including genetic mutations, endocrine disorders, and decline in immune function may increase the risk of developing BC.[3]
These results indicated that reduced miR-451 expression was a frequent event in human BC tissues and cells, which may be involved in breast carcinoma progression (Figures 1b and c)
We explored the role of miR-451 in the development of drug resistance in BC
Summary
BC will be diagnosed and 40 610 cancer deaths will be occurred in BC in 2017.2 The main carcinogenic factors, including genetic mutations, endocrine disorders, and decline in immune function may increase the risk of developing BC.[3]. Paclitaxel resistance (PR) is the main obstacle in the treatment of BC.[5] It is necessary to explore the molecular mechanism of chemoresistance and subsequently find a novel strategy to overcome such limitations for achieving better therapeutic effects in BC patients. Increasing evidence has demonstrated that miRNAs play important roles in the regulation of cell proliferation,[8] apoptosis,[9] EMT10 and metastasis[11] in various human cancers including BC. It has been reported that miR-451 was directly involved in the development of drug resistance of several types of cancers, such as non-small-cell lung cancer (NSCLC), colon carcinoma and glioblastoma.[17,18,19] these studies have showed that the potential role of miR-451 in chemoresistance in human cancer, the function of miR-451 in BC remains poorly understood
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