title: Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shaokun
authors.initials: S
authors.lastname: Shu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.|Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G2M9, Canada.
authors.forename: Housheng Hansen
authors.initials: HH
authors.lastname: He
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Witwicki
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Doris P
authors.initials: DP
authors.lastname: Tabassum
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Roberts
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michalina
authors.initials: M
authors.lastname: Janiszewska
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.affiliation: Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Doherty
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
authors.forename: Hisham
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Stover
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Muhammad B
authors.initials: MB
authors.lastname: Ekram
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
authors.forename: Clive
authors.initials: C
authors.lastname: D'Santos
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Dillon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McKeown
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Prakash K
authors.initials: PK
authors.lastname: Rao
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Duarte
authors.affiliation: Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Anders
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
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authors.initials: WT
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authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
authors.forename: Jason S
authors.initials: JS
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authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Long
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Meyer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Kornelia
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mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use*; D001667:Binding, Competitive / Q000187:drug effects; D047390:Casein Kinase II / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects*; D040901:Proteomics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D047390:Casein Kinase II; D018797:Cell Cycle Proteins; D002843:Chromatin; D056913:Mediator Complex Subunit 1; D009687:Nuclear Proteins; D010768:Phosphoserine; D054648:Protein Phosphatase 2; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C538855:MED1 protein, human