microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

Abstract

Triple Negative Breast Cancers (TNBC) is a heterogeneous disease at the molecular and clinical level with poor outcome. Molecular subclassification of TNBCs is essential for optimal use of current therapies and for development of new drugs. microRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance; investigation of their involvement in a TNBC cohort may reveal biomarkers for diagnosis and prognosis of TNBC. Here we stratified a large TNBC cohort into Core Basal (CB, EGFR and/or CK5, 6 positive) and five negative (5NP) if all markers are negative. We determined the complete miRNA expression profile and found a subset of miRNAs specifically deregulated in the two subclasses.We identified a 4-miRNA signature given by miR-155, miR-493, miR-30e and miR-27a expression levels, that allowed subdivision of TNBCs not only into CB and 5NP subgroups (sensitivity 0.75 and specificity 0.56; AUC=0.74) but also into high risk and low risk groups. We tested the diagnostic and prognostic performances of both the 5 IHC marker panel and the 4-miRNA expression signatures, which clearly identify worse outcome patients in the treated and untreated subcohorts. Both signatures have diagnostic and prognostic value, predicting outcomes of patient treatment with the two most commonly used chemotherapy regimens in TNBC: anthracycline or anthracycline plus taxanes. Further investigation of the patients' overall survival treated with these regimens show that regardless of IHC group subdivision, taxanes addition did not benefit patients, possibly due to miRNA driven taxanes resistance. TNBC subclassification based on the 5 IHC markers and on the miR-155, miR-493, miR-30e, miR-27a expression levels are powerful diagnostic tools. Treatment choice and new drug development should consider this new subtyping and miRNA expression signature in planning low toxicity, maximum efficacy therapies.

The role of microRNAs in gallbladder cancer

“…Elevated expression of miR-155 has been described in multiple cancers, reflecting tumor staging, progression and treatment outcomes (61)(62)(63)(64). In accordance with expectations, miR-155 acts as a vital oncogene in GBCs, as was reported by Kono et al (43).…”

Protective role of miR-155 in breast cancer through RAD51 targeting impairs homologous recombination after irradiation

“…Based on data availability we considered miR-155 expression in a subcohort of 93 TNBCs treated with both chemotherapy plus radiation and with radiation only (see Table S1 for demographic characteristics of the subcohort and ref. 31 for the characteristics of the whole cohort); miR-155 expression level positively correlated with the overall survival for patients [P = 0.031, hazard ratio 2.24, 95% confidence interval (CI) 1.08-4.51; Fig. 1A].…”

A Serum MicroRNA Signature Predicts Tumor Relapse and Survival in Triple-Negative Breast Cancer Patients

“…Even though other prognostic gene signatures have been developed from TNBC tissues (29)(30)(31)(32), our study is the first to identify a specific miRNA signature in the serum of patients with TNBC correlated with the high likelihood of tumor relapse. Furthermore, despite their molecular heterogeneity, all newly diagnosed basal-like/TNBC cases are treated with standard adjuvant combination chemotherapy, although with unsatisfactory results.…”