A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer

Abstract

Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. Objective: Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. Methodology and Results: Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50–65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. Conclusion: We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC.

The Unique Biology behind the Early Onset of Breast Cancer

“…Seven of these microRNAs were upregulated (miR-9, miR-210, miR-106a, miR-106b, miR-18b, miR-33b, and miR-518a-3p), and only one was downregulated (miR-372). The expression level of most of those deregulated microRNAs was associated with higher tumor size and TNM stage ( p -value < 0.05) [ 92 ].…”

“…The pattern of expression of the deregulated proteins was linked to the clinical parameters of EOBC. Higher expression of PRP1 and lower expression of RPS6KA1 were associated with positive lymph nodes status, whereas overexpression of RAF1 and underexpression of STAT5A were correlated with high TNM stage [ 92 ].…”

The versatile nature of miR-9/9* in human cancer

“…However, when upregulated it is associated with worse patient outcome and its viral overexpression in MCF-7 cells contributes to tamoxifen resistance. [ 37 , 38 ] The expression of miR-9 in ER + BC has recently been linked to the level of lncRNA taurine-upregulated gene 1 ( TUG1 ). It has been proposed that TUG1 and miR-9 may co-regulate each other to impact cell proliferation [ 39 ].…”

Ordering Quantiles through Confidence Statements

“…We consider it important to have a sound procedure to resolve them in order to deal with discrete ordinal data. We are also pursuing new applications of the method in biological data sets [25], in particular to the analysis of data with multiple groups and situations where some particular order of the groups is of great interest and importance.…”