Selective arm-usage of pre-miR-1307 dysregulates angiogenesis and contributes to breast cancer aggressiveness

Abstract

AbstractBreast cancer is the most common malignancy in women worldwide and the leading cause of cancer-related mortality in women Breast cancer aggressiveness can be regulated by miRNAs, which are encoded in the genome as pre-miRNAs. One pre-miRNA can give rise to several functionally distinct mature miRNA species. miR-1307-3p has been described to promote breast cancer progression. However, the impact of global overexpression of pre-miR-1307 has not been investigated in breast cancer, yet. Here, we found significant upregulation of the three mature miRNA species derived from pre-miR-1307 in breast cancer tissue from the TCGA-BRCA cohort. Surprisingly, the overexpression of pre-miR-1307 in basal-like breast cancer cell lines resulted in impaired xenograft growth and impaired angiogenesisin vivo.Mechanistically, we showed that overexpression specifically of miR-1307-5p caused alterations in the secretome of breast cancer cells and reduced endothelial cell sprouting. Of note, expression levels of miR-1307-5p were inversely correlated with endothelial cell fractions in human breast tumors and associated with improved prognosis, corroborating the anti-angiogenic function of the 5p arm of miR-1307. Importantly, arm usage of miR-1307 was highly correlated with arm usage patterns of several other miRNAs suggesting a common regulatory mechanism, which still needs to be uncovered. Taken together, miR-1307-5p negatively regulates angiogenesis in breast cancer and thereby antagonizes the oncogenic miR-1307-3p. Hence, our results emphasize the importance of future research focusing on the regulation of miRNA arm selection in cancer. The underlying mechanisms might ultimately serve as the basis for innovative therapeutic strategies shifting the balance towards tumor-suppressive miRNA species.