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MicroRNA-126 is Dysregulated in Cancer- Free Females Harboring Methylated BRCA1 Promoter through Up-Regulation of DNMTs

Background: Numerous microRNAs have been categorized as tumor suppressors that are often repressed by aberrant DNA methylation. Recently, BRCA1 promoter methylation in White Blood Cells (WBC) has been linked to elevated risk of developing breast cancer. In the present study, we aimed to investigative cancerrelated microRNA alterations in WBC harboring methylated BRCA1 promoter. Methods: The Human Cancer miRNA EpiTect Methyl II Signature PCR Array was used to study the methylation status of several cancer-related microRNA sequences. Real time RT-PCR was used to determine the levels of microRNA primary transcripts and DNMTs. The Stem-loop RT-PCR assay was also used to quantify the expression levels of mature microRNAs. Results: Out of 35 miRNAs, miR-126 was found to be hyper-methylated in WBC of breast cancer patients as well as in WBC of cancer-free females who harbored methylated BRCA1 (carriers). The methylation was associated with down regulation of the pre-miR-126 in WBC and lower levels of circulating mature miR-126 in the plasma. Strong positive correlation between the expression levels of both forms of miR-126s was observed in the carriers but not in cancer patients. Importantly, we have found higher mRNA expression of DNMT1, DNMT3a and DNMT3b in WBC of carriers compared to controls. Conclusion: Here, we have demonstrated that miR-126 is dysregulated in WBC of cancer-free females harboring methylated BRCA1 promoter. Importantly, our findings suggest that the up-regulation of DNMTs could be responsible for the aberrant methylation of both miR-126 and BRCA1 promoter in WBC.


Nisreen Al-Moghrabi, Nujoud Al-Yousef, Maram Al-Showimi and Lamyaa AlGhofaili

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