Identification of exosomal microrna targeting BRCA-deficient breast cancer

Abstract

Background: Several studies reported that BRCA mutation carriers had a higher recurrence rate and less favorable tumors than non-carriers. Exosomes are small membrane-derived vesicles that function to mediate cell-cell communication by transferring cancer promoting microRNAs (miRs). However, the selectivity of miRNA released from tumor-derived exosomes and its relevance in cancer treatment has not been studied. Methods: Exosomes were isolated from plasma of breast cancer patients and healthy individuals. Breast cancer-derived exosomal-miRNAs (exo-miRs) were profiled by RNA-sequencing and microarray. Real-time RT-PCR was used for validation in pre- and post-operative plasma, as well as primary tumor tissues. Characterization of exo-miR on cell proliferation was performed in exo-miR transfected cells. Result: BRCA-associated exo-miRNAs (miR-106a, miR-20a, miR-23a, miR-451 and miR-486) were identified from array data and further validated in BRCA-positive, BRCA-negative and healthy controls by real-time RT-PCR. In addition, the expression levels of miR-106a, miR-451 and miR-486 were lowered in post-operative plasma of BRCA-carriers than non-carriers High expression of exo-miR-106a, miR-20a, miR-23a, miR-451 and miR-486 were also seen in breast cancer cell lines (MB-231 and MB-468) relative to normal breast cells (MCF-10A). Importantly, expression of miR-451 was reduced after tumor resection in BRCA mutation carriers. Cells transfected with miR-451 inhibitor significantly reduced cell proliferation in breast cancer cells, suggesting that exosomes carrying miR-451 retard cancer cell growth. Conclusions: These findings suggest that exo-miR plays a critical role in breast cancer progression, and yet reduce its expression significantly suppressed tumor growth. This study provides a rationale for targeting exo-miR as an alternate therapeutic option for BRCA-associated tumors.