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BACKGROUND: miR-133a-3p has been recently discovered to be down-regulated in various human malignancies, including breast cancer, and reduced miR-133a-3p levels have been significantly associated with breast cancer cell growth and invasion. However, the regulatory mechanisms leading to abnormal expression of miR-133a-3p in breast cancer remain obscure. METHODS: qRT-PCR was applied to detect the expression of miR-133a-3p in breast cancer tissues and cell lines. Bisulfite sequencing was used to detect the degree of methylation of the miR-133a-3p promoter. The effects of miR-133a-3p on breast cancer in vitro were examined by cell proliferation assay, transwell assay, flow cytometry, and western blotting. Bioinformatic analysis, dual-luciferase assay and RIP assay were employed to identify the interaction between miR-133a-3p and MAML1. A xenograft model was used to show the metastasis of breast cancer cells. RESULTS: We confirmed that miR-133a-3p was silenced by DNA hypermethylation in breast cancer cell lines and tissues, which predicted poor prognosis in breast cancer patients, and reducing miR-133a-3p expression led to a significant increase in the migration, invasion, proliferation, and stemness of breast cancer cells in vitro. Mastermind-like transcriptional coactivator 1 (MAML1) was confirmed to be a target of miR-133a-3p involved in regulating breast cancer metastasis both in vitro and in vivo. Moreover, a series of investigations indicated that MAML1 initiated a positive feedback loop, which could up-regulate DNA methyltransferase 3A (DNMT3A) to promote hypermethylation of the miR-133a-3p promoter. CONCLUSION: Taken together, our findings revealed a novel miR-133a-3p/MAML1/DNMT3A positive feedback loop in breast cancer cells, which may become a potential therapeutic target for breast cancer.

Original publication

DOI

10.1186/s13046-019-1400-z

Type

Journal article

Journal

J exp clin cancer res

Publication Date

28/10/2019

Volume

38

Keywords

Breast cancer, DNA methylation, DNMT3A, MAML1, Metastasis, miR-133a-3p, Breast Neoplasms, Cell Line, Tumor, Cell Movement, DNA (Cytosine-5-)-Methyltransferases, Female, Gene Silencing, Humans, MicroRNAs, Neoplasm Metastasis, Transfection