title: The SWI/SNF ATPases Are Required for Triple Negative Breast Cancer Cell Proliferation.
abstract: The Brahma (BRM) and Brahma-related Gene 1 (BRG1) ATPases are highly conserved homologs that catalyze the chromatin remodeling functions of the multi-subunit human SWI/SNF chromatin remodeling enzymes in a mutually exclusive manner. SWI/SNF enzyme subunits are mutated or missing in many cancer types, but are overexpressed without apparent mutation in other cancers. Here, we report that both BRG1 and BRM are overexpressed in most primary breast cancers independent of the tumor's receptor status. Knockdown of either ATPase in a triple negative breast cancer cell line reduced tumor formation in vivo and cell proliferation in vitro. Fewer cells in S phase and an extended cell cycle progression time were observed without any indication of apoptosis, senescence, or alterations in migration or attachment properties. Combined knockdown of BRM and BRG1 showed additive effects in the reduction of cell proliferation and time required for completion of cell cycle, suggesting that these enzymes promote cell cycle progression through independent mechanisms. Knockout of BRG1 or BRM using CRISPR/Cas9 technology resulted in the loss of viability, consistent with a requirement for both enzymes in triple negative breast cancer cells.
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Qiong
authors: Q
authors: Wu
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Pasil
authors: P
authors: Madany
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Jacqueline
authors: J
authors: Akech
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Molecular Biology, Cell Biology and Biochemistry, Center for Computational Molecular Biology, Brown University, Providence, Rhode Island.|Department of Computer Science, Brown University, Providence, Rhode Island.
authors: Jason R
authors: JR
authors: Dobson
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Stephen
authors: S
authors: Douthwright
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, Vermont.
authors: Gillian
authors: G
authors: Browne
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Jennifer L
authors: JL
authors: Colby
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Georg E
authors: GE
authors: Winter
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors: James E
authors: JE
authors: Bradner
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Anatomy and Cell Biology, Rush University, Chicago, Illinois.
authors: Jitesh
authors: J
authors: Pratap
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Greenfield
authors: G
authors: Sluder
authors: Department of Pathology, Magee-Womens Hospital, Pittsburgh, Pennsylvania.
authors: Rohit
authors: R
authors: Bhargava
authors: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors: Simion I
authors: SI
authors: Chiosea
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Departments of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, Vermont.
authors: Janet L
authors: JL
authors: Stein
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, Vermont.
authors: Gary S
authors: GS
authors: Stein
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.|Department of Biochemistry and Vermont Cancer Center for Basic and Translational Research, University of Vermont College of Medicine, Burlington, Vermont.|Department of Orthopedics and Physical Rehabilitation, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Jane B
authors: JB
authors: Lian
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Jeffrey A
authors: JA
authors: Nickerson
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors: Anthony N
authors: AN
authors: Imbalzano
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D064113:CRISPR-Cas Systems; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; D004265:DNA Helicases