Abstract 4734: miR-9-5p expression in breast cancer correlates with hormone receptor status and affects patients survival
Authors: Barbano Raffaela , Pasculli Barbara , Rendina Michelina , Fontana Andrea , Fusilli Caterina , Copetti Massimiliano , Castellana Stefamo , Valori Vanna Maria , Morritti Maria , Graziano Paolo , Ciuffreda Luigi , Coco Michelina , Picardo Francesco , Mazza Tommaso , Evron Ella , Murgo Roberto , Maiello Evaristo , Esteller Manel , Fazio Vito Michele , Parrella Paola 
Published: July 2017

miR-9 (hsa-miR-9-5p, miR-9-5p) is a highly conserved microRNA (miRNA) primarily expressed in the central nervous system. The three promoters of miR-9 (miR-9-1 at 1q22, miR-9-2 at 5q14.3 and miR-9-3 at 15q26.1) are embedded within CpG islands, and hypermethylation in at least one of these regions has been reported in several tumor types, thus miR-9-5p has been designated as an epigenetically regulated miRNA. However, only a partial or none correlation between methylation status of miR-9 loci and miR-9-5p expression has been demonstrated so far. Furthermore, the expression levels of miR-9-5p resulted highly variable across different carcinomas and conflicting evidences also exist about its functional role within the tumor context. In light of this, we took the effort of clarifying the role of miR-9-5p in primary breast cancer tissues and of evaluating its potential as clinical relevant prognostic biomarker. We analysed miR-9-5p expression and miR-9 promoters methylation status in 129 breast cancer cases and 12 normal breast tissues (NBTs), by qRT-PCR and MSP respectively. Overall, miR-9-5p was increased in tumors compared to NBTs (P&lt;0.001). No significant correlation between promoter methylation and miR-9-5p expression was found either in tumors or in NBTs. Interestingly, miR-9-5p expression was inversely correlated with ER and PgR positivity (P=0.004 and P=0.003, respectively). Consistently, triple negative breast cancer (TNBC) showed the highest miR-9-5p levels and luminal subtype the lowest (P=0.04). The analysis of the TCGA Breast Cancer dataset (n=256) confirmed our results and further demonstrated that miR-9-5p was differentially expressed between the two luminal subtypes (P=0.009) and HER2-amplified compared to TNBCs (P&lt;0.0001). In Univariable Cox regression analysis miR-9-5p expression was significantly associated with higher risk of death (P=0.023). Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways. Our data suggest miR-9-5p may help refine the molecular classification of breast cancer subtypes and provide additional prognostic information.

Citation Format: Raffaela Barbano, Barbara Pasculli, Michelina Rendina, Andrea Fontana, Caterina Fusilli, Massimiliano Copetti, Stefamo Castellana, Vanna Maria Valori, Maria Morritti, Paolo Graziano, Luigi Ciuffreda, Michelina Coco, Francesco Picardo, Tommaso Mazza, Ella Evron, Roberto Murgo, Evaristo Maiello, Manel Esteller, Vito Michele Fazio, Paola Parrella. miR-9-5p expression in breast cancer correlates with hormone receptor status and affects patients survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2017-4734