title: MicroRNA signatures in hereditary breast cancer.
abstract: This study aims to identify signatures of miR associated with hereditary, BRCA1 or BRCA2 mutation positive breast cancer (BC), and non-hereditary BC, either sporadic (SBC) or non-informative (BRCAX). Moreover, we search for signatures associated with tumor stage, immunohistochemistry and tumor molecular profile. Twenty formalin fixed paraffin embedded (FFPE) BCs, BRCA1, BRCA2, BRCAX and SBC, five per group were studied. Affymetrix platform miRNA v.3.0 was used to perform miR expression analysis. ER, PR, HER2 and Ki67 protein expression was analyzed by immunohistochemistry. BRCA1, BRCA2 and RASSF1 methylation analysis, AURKA copy number variations, and BRCA1 and BRCA2 deletions, were studied by MLPA. We validated eight of the miR selected by the arrays in 77 BCs by qRT-PCR. The miR profiles associated with tumor features were studied applying the Sparse Partial Least Squares Discriminant Analysis. MiR discrimination capability to distinguish hereditary and non-hereditary BC was analyzed by the discriminant function. With 15 out of 1,733 hsa-miRs, it was possible to differentiate the four groups. BRCA1, BRCA2 and SBC were associated with clusters of hyper-expressed miRs, and BRCAX with hypo-expressed miRs. Hsa-miR-4417 and hsa-miR-423-3p expressions (included among the eight validated miRs) differentiated 70.1 % of hereditary and non-hereditary BCs. We found miR profiles associated with tumor features like node involvement, histological grade, ER, PR and HER2 expression. Regarding molecular parameters, we only found a weak association of miRs in BC harboring losses in AURKA. We conclude that array miR expression profiles can differentiate the four study groups using FFPE BC. However, miRs expression estimated by qRT-PCR differentiates only hereditary and non-inherited BCs. The miR expression array is a simple and rapid approach that could be useful to facilitate the identification of those SBC carrying genetic or epigenetic changes in BRCA genes responsible of BRCA-like phenotype. These patients could benefit from the treatment with PARP inhibitors.
authors.affiliation: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe, Escuela de Enfermería 7ª planta. Avd. Campanar 21, 46009, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Murria Estal
authors.forename: Sarai
authors.initials: S
authors.lastname: Palanca Suela
authors.forename: Inmaculada
authors.initials: I
authors.lastname: de Juan Jiménez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Egoavil Rojas
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.forename: María José
authors.initials: MJ
authors.lastname: Juan Fita
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: Sánchez Heras
authors.forename: Angel
authors.initials: A
authors.lastname: Segura Huerta
authors.forename: Isabel
authors.initials: I
authors.lastname: Chirivella González
authors.forename: Dolors
authors.initials: D
authors.lastname: Sánchez-Izquierdo
authors.forename: Marta
authors.initials: M
authors.lastname: Llop García
authors.forename: Eva
authors.initials: E
authors.lastname: Barragán González
authors.forename: Pascual
authors.initials: P
authors.lastname: Bolufer Gilabert
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D035683:MicroRNAs