title: Integration of mRNA expression profile, copy number alterations, and microRNA expression levels in breast cancer to improve grade definition.
abstract: Defining the aggressiveness and growth rate of a malignant cell population is a key step in the clinical approach to treating tumor disease. The correct grading of breast cancer (BC) is a fundamental part in determining the appropriate treatment. Biological variables can make it difficult to elucidate the mechanisms underlying BC development. To identify potential markers that can be used for BC classification, we analyzed mRNAs expression profiles, gene copy numbers, microRNAs expression and their association with tumor grade in BC microarray-derived datasets. From mRNA expression results, we found that grade 2 BC is most likely a mixture of grade 1 and grade 3 that have been misclassified, being described by the gene signature of either grade 1 or grade 3. We assessed the potential of the new approach of integrating mRNA expression profile, copy number alterations, and microRNA expression levels to select a limited number of genomic BC biomarkers. The combination of mRNA profile analysis and copy number data with microRNA expression levels led to the identification of two gene signatures of 42 and 4 altered genes (FOXM1, KPNA4, H2AFV and DDX19A) respectively, the latter obtained through a meta-analytical procedure. The 42-based gene signature identifies 4 classes of up- or down-regulated microRNAs (17 microRNAs) and of their 17 target mRNA, and the 4-based genes signature identified 4 microRNAs (Hsa-miR-320d, Hsa-miR-139-5p, Hsa-miR-567 and Hsa-let-7c). These results are discussed from a biological point of view with respect to pathological features of BC. Our identified mRNAs and microRNAs were validated as prognostic factors of BC disease progression, and could potentially facilitate the implementation of assays for laboratory validation, due to their reduced number.
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cava
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bertoli
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Ripamonti
authors.affiliation: Department of Informatics, Systems and Communications, University of Milan-Bicocca, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Mauri
authors.affiliation: Department of Informatics, Systems and Communications, University of Milan-Bicocca, Milan, Italy.
authors.forename: Italo
authors.initials: I
authors.lastname: Zoppis
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Pasquale Anthony
authors.initials: PA
authors.lastname: Della Rosa
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Gilardi
authors.affiliation: Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Castiglioni
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D060787:Neoplasm Grading; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger