RESUMEN
Inappropriate expression or activation of transcription factors can drive patterns of gene expression, leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we used chromatin immunoprecipitation followed by deep sequencing to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared with B-cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a signal transducer and activator of transcription3 inhibitor provided enhanced cell killing in triple-negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Amplificación de Genes , Peptidomiméticos/farmacología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/metabolismo , Sinergismo Farmacológico , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células MCF-7 , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-bcl-6 , Pirrolidinas/farmacología , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
The effect of dietary wheat bran and dehydrated citrus fiber on carcinogenesis of the colon and small intestine was studied in male F344 rats. Weanling rats were fed semi-purified diets containing 5% fat and 15% wheat bran or citrus fiber. At 7 weeks of age, all animals, except vehicle-treated controls, received weekly sc injections of 8 mg azoxymethane (AOM)/kg body weight for 10 weeks. The AOM- or vehicle-treated groups were autopsied 20 weeks after the last injection of AOM. The animals fed the wheat bran or citrus fiber diet and treated with AOM had a lower incidence (number of animals with tumors) and multiplicity (number of tumors/tumor-bearing animal) of colon tumors and tumors of the small intestine than did those fed the control diet and treated with AOM. Animals fed the diet containing wheat bran developed fewer adenomas and adenocarcinomas of the colon than did the rats fed the control diet; the number of adenomas but not the number of adenocarcinomas was reduced in rats fed the citrus pulp diet. This study thus indicates that diets containing wheat bran and citrus fiber reduced the risk of intestinal cancer.