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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Mucinous / drug therapy
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Adenocarcinoma, Mucinous / genetics*
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Adenocarcinoma, Mucinous / metabolism
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Adenocarcinoma, Mucinous / pathology
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Antineoplastic Agents / pharmacology
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Azacitidine / pharmacology
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Carcinoma, Ductal, Breast / drug therapy
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Carcinoma, Ductal, Breast / genetics*
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Carcinoma, Ductal, Breast / metabolism
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Carcinoma, Ductal, Breast / pathology
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Carcinoma, Lobular / drug therapy
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Carcinoma, Lobular / genetics*
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Carcinoma, Lobular / metabolism
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Carcinoma, Lobular / pathology
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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DNA Methylation
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Estrogen Receptor alpha / deficiency
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Estrogen Receptor alpha / genetics
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Female
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Fluorouracil / pharmacology
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Gene Expression Regulation, Neoplastic*
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Humans
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Lymphatic Metastasis
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Methotrexate / pharmacology
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Organ Specificity
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Promoter Regions, Genetic
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Purine-Nucleoside Phosphorylase / antagonists & inhibitors
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Purine-Nucleoside Phosphorylase / genetics*
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Purine-Nucleoside Phosphorylase / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptor, ErbB-2 / deficiency
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Receptor, ErbB-2 / genetics
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Receptors, Progesterone / deficiency
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Receptors, Progesterone / genetics
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Signal Transduction
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Triple Negative Breast Neoplasms / drug therapy
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Triple Negative Breast Neoplasms / genetics*
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology
Substances
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Antineoplastic Agents
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Cyclin-Dependent Kinase Inhibitor p16
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Estrogen Receptor alpha
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RNA, Small Interfering
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Receptors, Progesterone
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Purine-Nucleoside Phosphorylase
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5'-methylthioadenosine phosphorylase
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ERBB2 protein, human
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Receptor, ErbB-2
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Azacitidine
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Fluorouracil
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Methotrexate
Grants and funding
This work was supported by Programa de Apoio a Nucleos de Excelencia (PRONEX), and Conselho Nacional de Ensino e Pesquisa, CNPq. Brazil. Protocolo 24652; convenio 251/2013. Authors: EMSFR IJC.