Abstract
Abstract Heterogeneity of breast cancer, specifically in triple negative (TN) tumors represents a clinical challenge which deserves further research in order to understand tumor biology and improve treatment options. MicroRNAs are small non-coding RNAs that regulates gene expression and play crucial roles in breast carcinogenesis. In order to analyze the heterogeneity and identify different subgroups of TN tumors, we analyzed the genome-wide microRNA expression patterns of 1105 mature miRNAs in 98 FFPE TN and 15 additional tumors with other immunophenotypes, using the Affymetrix Gene Expression miRNA microarray v2.0. Bioinformatic analysis with the non-supervised Consensus Clustering algorithm defined 4 groups, each of them showing association with clinically relevant parameters like the presence of metastases and survival. Several cellular pathways like cell proliferation, programmed cell death and motility are enriched in each of the microRNA expression defined groups. Based on miRNAs expression profiles between TN tumors and other inmunophenotypes (N=15 tumors), 3 miRNAs (miR-125b-2-3p, miR-342-3p -both of them down-regulated in TN tumors- and miR-660 -over-expressed-) were chosen for further functional studies in cellular models to better define their relationship with the biology and phenotype of triple negative tumors. After transfections in TN cell lines (MDA MB 231 and 468) a genomic evaluation of their transcriptional targets was made with the Human Gene St 1.0 array (Affymetrix), this data, together with in silico analysis, defined at least 25 mRNAs that are regulated by those miRNAs. Through this approach, we found that different patterns of mRNA targets emerge for each cellular model, reflecting their distinctive molecular and cellular features. The transcriptional targets identified, are involved in different tumorigenic pathways, such as activation of immune responses, regulation of apoptosis, cell motility and adhesion. Some of these results have been validated by other methodologies like measurement of Ki67 for proliferation, Annexin V for apoptosis and cell cycle status. Our data identified the altered expression of microRNAs that reveals the existence of 4 subgroups with different prognostic values among TN tumors. Furthermore, we performed the characterization of 3 miRNAs with aberrant expression in TN tumors that regulate cancer-related mRNAs and whose role in TN breast cancer has not been previously described. Together, these findings confirm the participation of miRNAs as regulators of cancer programs in triple negative tumors. Citation Format: Sandra L. Romero-Cordoba, Rosa Rebollar-Vega, Valeria Quintanar-Jurado, Alfredo Hidalgo-Miranda, Sergio Rodriguez-Cuevas, Veronica Bautista-Pina, Antonio Maffuz-Aziz. miRNA profiles identify different subgroups of triple negative tumors and reveal novel miRNA-mRNA interactions in breast cancer tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4370. doi:10.1158/1538-7445.AM2014-4370
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