title: Characterization of MTAP Gene Expression in Breast Cancer Patients and Cell Lines.
abstract: MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors´ MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC.
authors.affiliation: Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Sarah Franco Vieira
authors.initials: SF
authors.lastname: de Oliveira
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche ''Mario Negri", Milan, Lombardia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Ganzinelli
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche ''Mario Negri", Milan, Lombardia, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Chilà
authors.affiliation: Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Serino
authors.affiliation: Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Marcos Euzébio
authors.initials: ME
authors.lastname: Maciel
authors.affiliation: Department of Mastology, Breast Unit, Hospital Nossa Senhora das Graças, Curitiba, Paraná, Brazil.
authors.forename: Cícero de Andrade
authors.initials: Cde A
authors.lastname: Urban
authors.affiliation: Department of Mastology, Breast Unit, Hospital Nossa Senhora das Graças, Curitiba, Paraná, Brazil.
authors.forename: Rubens Silveira
authors.initials: RS
authors.lastname: de Lima
authors.affiliation: Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Iglenir João
authors.initials: IJ
authors.lastname: Cavalli
authors.affiliation: Laboratorio di Oncologia Molecolare Senologica, U. O. Multidisciplinare di Patologia Mammaria, A. O. Istituti Ospitalieri di Cremona, Cremona, Lombardia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche ''Mario Negri", Milan, Lombardia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche ''Mario Negri", Milan, Lombardia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.affiliation: Department of Genetics, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Enilze Maria de Souza Fonseca
authors.initials: EM
authors.lastname: Ribeiro
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000494:pharmacology; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001374:Azacitidine; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047628:Estrogen Receptor alpha; D005472:Fluorouracil; D008727:Methotrexate; D011683:Purine-Nucleoside Phosphorylase; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; C021784:5'-methylthioadenosine phosphorylase; C508053:ERBB2 protein, human