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microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers
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Abstract
Pierluigi Gasparini1,*, Luciano Cascione1,8,*, Matteo Fassan1,2,*, Francesca Lovat1, Gulnur Guler3, Serdar Balci4, Cigdem Irkkan5, Carl Morrison6, Carlo M. Croce1, Charles L. Shapiro7, Kay Huebner1
1 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA
2 ARC-NET Research Centre, University and Hospital Trust of Verona, Verona, Italy
3 Department of Pathology, Hacettepe University, Ankara,Turkey
4 Department of Pathology, Yildirim Beyazit University, Ankara Ataturk Research and Training Hospital, Ankara, Turkey
5 Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital of the Ministry of Health
6 Department of Pathology, Roswell Park Cancer Institute, Basic Science Building, Elm and Carlton Streets Buffalo, NY
7 Division of Medical Oncology and the Breast Program James Cancer Hospital and Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
8 IOR, Institute of Oncology Research, Bellinzona, Switzerland
* These authors contributed equally to the work
Correspondence:
Pierluigi Gasparini, email:
Keywords: Triple Negative breast cancer, microRNA, five markers, prognosis, treatments, outcome
Received: December 11, 2013 Accepted: January 19, 2014 Published: January 21, 2014
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 investigations 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.
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