Abstract P5-07-14: miR-17-92 cluster, an oncogenic microRNA cluster acts as a context dependent tumour suppressor in breast cancer

Abstract

Abstract Background: The miR-17-92 is an oncogenic miRNA cluster that generate six mature miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1. Accumulating evidences indicate the oncogenic role of the miR-17-92 cluster in human cancers. Amplification of 13q31-q32, which is the locus of the miR-17-92 cluster, have been reported in haematopoietic malignancies, such as B cell lymphoma. In contrast, MIR17HG was deleted in 21.9% of breast cancers and loss of heterozygosity at 13q12-q13 was associated with poor prognosis in breast cancer. This oncogenic miRNA cluster is deferentially expressed in various cancer. Since, miR-17-92 cluster shows differential expression among the cancers types, it is hypothesized that biological function may also vary depending on the context. Indeed, this cluster has been shown to act a tumour suppressor in some cancers. However, the functional role of this cluster in the subtypes of breast cancer remains largely unknown. Methods: The oncomine datasets were analysed for expression of MIR17HG in breast cancer at parameters p-value threshold of 0.01 with minimum 2-fold change. We generated stable sub-clones of MCF7, T47D, SKBR3 and MDA-MB231 cells overexpressing miR-17-92 cluster by transducing with lentivirus expressing miR-17-92. Proliferation was assessed by MTS assay and colony forming assay. Cell migration was tested using scratch method. Invasion potentiality was monitored by using matrigel Boyden chamber invasion assay. For drug response analysis, control and microRNA overexpressing sub-clones were exposed to different chemotherapeutic agents at different concentrations followed by MTS assay at different time intervals. Association of miRNAs belonging to miR-17-92 with outcome in breast cancer was determined by Kaplan-Meier analysis on METABRIC dataset. Results: We observed that expression of MIR17HG was increased in tissues and cell lines from triple negative breast cancer (TNBC) but decreased in the tissues and cell lines from the estrogen receptor (ER)-positive breast cancer. Our results showed that ectopic expression of miR-17-92 cluster significantly suppressed cell proliferation, colony formation, migration and invasion of ER-positive (MCF7, T47D) and HER2-enriched (SKBR3) cells whereas it enhanced cell proliferation, colony formation, migration and invasion in (TNBC) MDA-MB 231 cells. Further, we found that expression of miR-17-92 cluster sensitized MCF7 cells whereas it rendered SKBR3 cells resistant to chemotherapeutic compounds. Higher expression of five miRNAs of this cluster was associated with better relapse free survival (RFS) in (miR-17, miR-19a, miR-20a, miR-19b and miR-92) Luminal A subtype whereas three miRNAs of this cluster were associated with poor RFS in (miR-17, miR-18a and miR-92) HER2-enriched and (miR-17, miR-19b and miR-92) TNBC subtypes. Conclusions: Taken together our results suggest that miR-17-92 cluster acts as a tumour suppressor in ER-positive and HER2-enriched breast cancer cells but shows oncogenic role in TNBC. Our observations underscore the functional complexity of miR-17-92 in a context-dependent and cell type-dependent manner, and more investigations are warranted to fully explore the functional complexity of miR-17-92 in subtypes of breast cancer. Citation Format: Hossain MM, Arabkari V, Barua D, Gupta A, Islam MN, Gupta S. miR-17-92 cluster, an oncogenic microRNA cluster acts as a context dependent tumour suppressor in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-14.