title: 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 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.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Gulnur
authors.initials: G
authors.lastname: Guler
authors.forename: Serdar
authors.initials: S
authors.lastname: Balci
authors.forename: Cigdem
authors.initials: C
authors.lastname: Irkkan
authors.forename: Carl
authors.initials: C
authors.lastname: Morrison
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D053555:Keratin-5 / Q000032:analysis; D053553:Keratin-6 / Q000032:analysis; D008727:Methotrexate / Q000008:administration & dosage; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D053555:Keratin-5; D053553:Keratin-6; C524942:MIRN155 microRNA, human; C531388:MIRN27 microRNA, human; C546086:MIRN30b microRNA, human; C555448:MIRN493 microRNA, human; D035683:MicroRNAs; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D004317:Doxorubicin; D003520:Cyclophosphamide; D066246:ErbB Receptors; D017239:Paclitaxel; D005472:Fluorouracil; D008727:Methotrexate