title: The transcriptional modulator BCL6 as a molecular target for breast cancer therapy.
abstract: 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.
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Walker
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nicolais
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Giannopoulou
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
authors.forename: O
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Melnick
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Frank
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D057786:Peptidomimetics / Q000494:pharmacology*; D051560:Proto-Oncogene Proteins c-bcl-6; D011759:Pyrrolidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000096926:Benzenesulfonamides
chemical_list: D004268:DNA-Binding Proteins; D057786:Peptidomimetics; D051560:Proto-Oncogene Proteins c-bcl-6; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; C084103:BCL6 protein, human; C528327:fedratinib; D000096926:Benzenesulfonamides