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Bone morphogenetic protein 4 induced miRNA expression in breast cancer cell lines

ABSTRACT: Bone morphogenetic protein 4 (BMP4) is a remarkably powerful inhibitor of breast cancer cell proliferation, but is also able to induce breast cancer cell migration in certain cellular contexts. Previous data demonstrate that BMP4 controls the transcription of a variety of protein coding genes, but not much is known about microRNAs (miRNA) regulated by BMP4. In this study, miRNA expression patterns following BMP4 treatment were determined in one mammary epithelial and seven breast cancer cell lines using microarrays. The analysis identified 20 to 128 differentially expressed miRNAs in individual cell lines with emphasis on upregulation over downregulation. Four miRNAs (miR-16-5p, miR-106b-5p, miR-23a-3p and miR-23b-3p) were commonly induced in a subset of breast cancer cells upon BMP4 treatment and inhibition of their expression resulted in an increase in BT-474 cell number, indicating that they possess tumor suppressive properties. Yet no major change was detected when the cells were simultaneously treated with BMP4, and thus these miRNAs do not act as the main mediators of BMP4-induced growth reduction. MiR-16-5p and miR-106b-5p were elevated in MDA-MB-231 cells that respond to BMP4 with increased migration. Their inhibition, in combination with BMP4 treatment, resulted in enhanced MDA-MB-231 cell migration, suggesting that miR-16-5p and miR-106b-5p are engaged in BMP4-induced motility. Taken together, we have shown for the first time that in breast cancer cells BMP4 induces variable miRNA expression patterns.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70480 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA288968

REPOSITORIES: GEO

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Project description:Accumulating evidence indicates that human circulating microRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers in various cancers. We aimed to explore novel miRNA biomarkers in the blood of breast cancer patients based on miRNA profiling. A miRCURY™ LNA Array was used to identify differentially altered miRNAs in the whole blood of breast cancer patients (n = 6) and healthy controls (n = 6). Levels of candidate miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in whole blood specimens of 15 breast cancer patients and 13 age-matched healthy control individuals. The miRWalk database was used to predict miRNA targets and the DAVID tool was used to identify significant enrichment pathways. A total of 171 differentially expressed miRNAs were identified by microarray, including 169 up-regulated and 2 down-regulated miRNAs in breast cancer. Five upregulated miRNAs (miR-30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p) were confirmed by qRT-PCR. The areas under the receiver operating characteristic curve of miR-30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p were 0.9333, 0.7692, 0.7590, 0.8256, and 0.8128, respectively. A total of 855 genes were predicted to be targeted by the five miRNAs, and the one cut domain family member 2 gene (ONECUT2) was a shared target of the five miRNAs. Analysis of publicly available data revealed that these dysregulated miRNAs and target genes were associated with the survival of breast cancer patients. Furthermore, the five miRNAs were significantly enriched in numerous cancer-related pathways, including “MicroRNAs in cancer”, “Pathways in cancer”, “FoxO signaling pathway”, “Ras signaling pathway”, “Rap1 signaling pathway”, “MAPK signaling pathway”, and “PI3K-Akt signaling pathway”. Our data support the potential of the five identified miRNAs as novel biomarkers for the detection of breast cancer, and indicate that they may be involved in breast cancer development and progression.

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Bone morphogenetic protein 4 induced miRNA expression in breast cancer cell lines

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