RESUMO
During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Histona-Lisina N-Metiltransferase/genética , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Análise por Conglomerados , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Fenótipo , Prognóstico , Ligação Proteica , Curva ROC , Fatores de Transcrição da Família Snail/metabolismoRESUMO
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.
Assuntos
Reparo do DNA , Epigênese Genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Dipiridamol/metabolismo , Feminino , Antagonistas do Ácido Fólico/farmacologia , Histonas/metabolismo , Humanos , Células MCF-7 , Metilação/efeitos dos fármacos , Metilação/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: The aim of this study was to analyze the impact of surgical site infections (SSI) in patients who underwent radical cystectomy, in terms of excess hospital mortality, stay prolongation and cost overruns. MATERIAL AND METHODS: A retrospective observational study was conducted on a sample of patients who underwent radical cystectomy as recorded in the basic minimum data sets of 87 Spanish hospitals from 2008-2010. RESULTS: We studied 4377 patients who underwent radical cystectomy (3904 men and 473 women) of whom 849 (19.4%) experienced an SSI. The patients with SSI were predominantly men, elderly and had a higher prevalence of alcohol-related disorders and more comorbidities. The patients with SSI had significant excess mortality (125.6%), undue stay prolongation (17.8 days) and cost overruns (14,875.70 euros). CONCLUSIONS: After controlling for demographic variables, hospital type, addiction disorders and comorbidities using multivariate pairing, the onset of SSI in patients who underwent radical cystectomy significantly increased the mortality, stay and cost. Certain preventive measures already established in previous studies could reduce the incidence of SSI and its healthcare and financial impact.