Differential expression, function and prognostic value of miR-17-92 cluster in ER-positive and triple-negative breast...

Recent evidence has shown that the miR-17-92 cluster can function either as oncogene or tumor suppressor in human cancers. The function of miR-17-92 in subtypes of breast cancer remains largely unknown. The expression of miR-17-92 is elevated in triple negative breast cancer (TNBC) but reduced in estrogen receptor (ER)-positive breast cancer (ERPBC). We show that increased expression of miRNAs belonging to the miR-17-92 cluster is associated with poor outcome in TNBC, whereas the expression of miR-17-92 miRNAs is with good outcome in ERPBC. We show that ectopic expression of miR-17-92 inhibited cell growth and invasion of ER-positive and HER2-enriched cells. On the contrary, miR-17-92 expression enhanced cell growth and invasion of TNBC cells. Further, we found that miR-17-92 expression sensitized MCF7 cells to chemotherapeutic compounds, whereas it rendered SKBR3 cells resistant to them. We found that expression of ADORA1 was reduced by miR-17-92-expressing breast cancer cells, specifically in ERPBC. We observed an inverse correlation between the expression of ADORA1 and miR-17-92 in human breast cancer. Treatment with DPCPX, a selective ADORA1 antagonist, abolished the difference in the growth of control and miR-17-92 overexpressing MCF7 cells and identified ADORA1 as a key functional target of miR-17-92 in ERPBC. Furthermore, increased expression of ADORA1 in ERPBC is associated with a poor outcome. Our observations underscore the context-dependent role of miR-17-92 in breast cancer subtypes and suggest that miR-17-92 could serve as novel prognostic markers in breast cancer.