title: Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin.
abstract: Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPβ expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPβ-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.
authors.affiliation: Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Damiano
authors.affiliation: Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Stewart
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Cohet
authors.affiliation: Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Mouw
authors.affiliation: Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: Department of Pathology, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Debnath
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Reisman
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Nickerson
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Imbalzano
authors.affiliation: 1] Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California-San Francisco, San Francisco, CA, USA [2] Department of Anatomy, Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D039482:Integrin alpha5 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D039482:Integrin alpha5; D034741:RNA, Small Interfering; C084011:SMARCA2 protein, human; D014157:Transcription Factors