Abstract
Triple negative breast cancer (TNBC) is a heterogeneous disease at the molecular, pathologic and clinical levels. To stratify TNBCs, we determined microRNA (miRNA) expression profiles, as well as expression profiles of a cancer-focused mRNA panel, in tumor, adjacent non-tumor (normal) and lymph node metastatic lesion (mets) tissues, from 173 women with TNBCs; we linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify clinically and genetically different TNBC subclasses. We also assessed miRNA signatures as potential regulators of TNBC subclass-specific gene expression networks defined by expression of canonical signal pathways.Tissue specific miRNAs and mRNAs were identified for normal vs tumor vs mets comparisons. miRNA signatures correlated with prognosis were identified and predicted anti-correlated targets within the mRNA profile were defined. Two miRNA signatures (miR-16, 155, 125b, 374a and miR-16, 125b, 374a, 374b, 421, 655, 497) predictive of overall survival (P = 0.05) and distant-disease free survival (P = 0.009), respectively, were identified for patients 50 yrs of age or younger. By multivariate analysis the risk signatures were independent predictors for overall survival and distant-disease free survival. mRNA expression profiling, using the cancer-focused mRNA panel, resulted in clustering of TNBCs into 4 molecular subclasses with different expression signatures anti-correlated with the prognostic miRNAs.Our findings suggest that miRNAs play a key role in triple negative breast cancer through their ability to regulate fundamental pathways such as: cellular growth and proliferation, cellular movement and migration, Extra Cellular Matrix degradation. The results define miRNA expression signatures that characterize and contribute to the phenotypic diversity of TNBC and its metastasis.
Highlights
MiRNAs are small (19–25 nucleotides), non-coding RNAs that reduce the abundance and translational efficiency of mRNAs and play a major role in regulatory networks, influencing diverse biological processes [1,2] through effects of individual miRNAs on translation of multiple mRNAs
Results miRNA expression profiles differentiate among adjacent normal breast and Triple negative breast cancer (TNBC) tissues The profiles of 224 samples, 165 primary cancer-derived RNAs and 59 normal RNAs from patients with a median age of 51 years were considered
Summary of dysregulated miRNAs among the tissue classes The Venn diagram (Fig. 1) summarizes the number of differentially expressed miRNAs in the three tissue classes. 13 miRNAs (Fig. 1 B) represent the expression pathways dysregulated as cells progress from normal to primary TNBC
Summary
MiRNAs are small (19–25 nucleotides), non-coding RNAs that reduce the abundance and translational efficiency of mRNAs and play a major role in regulatory networks, influencing diverse biological processes [1,2] through effects of individual miRNAs on translation of multiple mRNAs. Triple-negative breast cancers are defined by a lack of expression of estrogen receptor (ESR1), progesterone receptor (PGR1), and ERBB2 receptor. This subgroup accounts for 15% of all types of breast cancer and is an aggressive form with limited treatment options. We have used the nanoString nCounter platform (Seattle, WA, USA) to profile both miRNA and mRNA expression (nanoString Cancer Reference panel) using the same RNA sample from each breast cancer patient. We emphasized the joint analysis of miRNA and mRNA data, and thoroughly analyzed anti-correlations between miRNA and mRNA expression data
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