title: Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer.
abstract: BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinico-pathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorphism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors.
authors.affiliation: IHEM-CCT-CONICET Mendoza and National University of Cuyo, Mendoza, Argentina. mbranham@fcm.uncu.edu.ar.
authors.forename: M T
authors.identifier: http://orcid.org/0000-0003-0362-0240
authors.initials: MT
authors.lastname: Branham
authors.affiliation: IHEM-CCT-CONICET Mendoza and National University of Cuyo, Mendoza, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Campoy
authors.affiliation: IHEM-CCT-CONICET Mendoza and National University of Cuyo, Mendoza, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Laurito
authors.affiliation: IANIGLA-CCT-CONICET Mendoza, Mendoza, Argentina.
authors.forename: R
authors.initials: R
authors.lastname: Branham
authors.affiliation: IHEM-CCT-CONICET Mendoza and National University of Cuyo, Mendoza, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Urrutia
authors.affiliation: Gineco-Mamario Institute of Mendoza, Mendoza, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Orozco
authors.affiliation: Gineco-Mamario Institute of Mendoza, Mendoza, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Gago
authors.affiliation: GI Research Unit, Division of Gastroenterology and Hepatology, Epigenomics Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, USA.
authors.forename: R
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: IHEM-CCT-CONICET Mendoza and National University of Cuyo, Mendoza, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Roqué
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Aberrant DNA methylation; BRCAness; Breast tumors; ID4