title: Targeting the epigenetics of the DNA damage response in breast cancer.
abstract: Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia 30100, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Montenegro
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia 30100, Spain.
authors.forename: R
authors.initials: R
authors.lastname: González-Guerrero
authors.affiliation: Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford OX3 7DQ, UK.
authors.forename: L
authors.initials: L
authors.lastname: Sánchez-del-Campo
authors.affiliation: Department of Surgery, University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, Murcia 30120, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Piñero-Madrona
authors.affiliation: Translational Cancer Research Group, University Hospital Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, Murcia 30120, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cabezas-Herrera
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia 30100, Spain.
authors.forename: J N
authors.initials: JN
authors.lastname: Rodríguez-López
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D019313:BRCA1 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004176:Dipyridamole / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008745:Methylation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002843:Chromatin; D005493:Folic Acid Antagonists; D006657:Histones; D012097:Repressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D004176:Dipyridamole; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases