title: TGF-β-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition.
abstract: ID genes are required for breast cancer colonization of the lungs, but the mechanism remains poorly understood. Here, we show that Id1 expression induces a stem-like phenotype in breast cancer cells while retaining epithelial properties, contrary to the notion that cancer stem-like properties are inextricably linked to the mesenchymal state. During metastatic colonization, Id1 induces a mesenchymal-to-epithelial transition (MET), specifically in cells whose mesenchymal state is dependent on the Id1 target protein Twist1, but not at the primary site, where this state is controlled by the zinc finger protein Snail1. Knockdown of Id expression in metastasizing cells prevents MET and dramatically reduces lung colonization. Furthermore, Id1 is induced by transforming growth factor (TGF)-β only in cells that have first undergone epithelial-to-mesenchymal transition (EMT), demonstrating that EMT is a prerequisite for subsequent Id1-induced MET during lung colonization. Collectively, these studies underscore the importance of Id-mediated phenotypic switching during distinct stages of breast cancer metastasis.
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA; Department of Molecular Biology, Weill Cornell Medical College, 445 East 69(th) Street, New York, NY 10021, USA.
authors: Marko
authors: M
authors: Stankic
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA; Department of Molecular Biology, Weill Cornell Medical College, 445 East 69(th) Street, New York, NY 10021, USA.
authors: Svetlana
authors: S
authors: Pavlovic
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA.
authors: Yvette
authors: Y
authors: Chin
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Edi
authors: E
authors: Brogi
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA; Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA 90095, USA.
authors: David
authors: D
authors: Padua
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Larry
authors: L
authors: Norton
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Joan
authors: J
authors: Massagué
authors: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 415 East 68(th) Street, New York, NY 10065, USA. Electronic address: r-benezra@ski.mskcc.org.
authors: Robert
authors: R
authors: Benezra
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1