title: Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients.
abstract: miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR-9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways.
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Barbano
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasculli
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Michelina
authors.initials: M
authors.lastname: Rendina
authors.affiliation: Unit of Biostatistics IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Unit of Bioinformatics IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: Unit of Biostatistics IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: Unit of Bioinformatics IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Castellana
authors.affiliation: Oncology Department IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Vanna Maria
authors.initials: VM
authors.lastname: Valori
authors.affiliation: Oncology Department IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Morritti
authors.affiliation: Pathology Unit IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Graziano
authors.affiliation: Breast Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Ciuffreda
authors.initials: C
authors.lastname: Luigi
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Michelina
authors.initials: M
authors.lastname: Coco
authors.affiliation: Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Picardo
authors.affiliation: Unit of Bioinformatics IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Assaf Harofeh Medical Center Zerifin, Affiliated with Tel Aviv University, Sakler School of Medicine, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Evron
authors.affiliation: Breast Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Murgo
authors.affiliation: Oncology Department IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Evaristo
authors.initials: E
authors.lastname: Maiello
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.|Laboratory of Genetic and Clinical Pathology, University Campus Bio-Medico of Rome, Italy.
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
authors.affiliation: Laboratory of Oncology IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Parrella
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D004967:Estrogens / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004967:Estrogens; C541874:MIRN92 microRNA, human; D035683:MicroRNAs