title: Basonuclin-1 modulates epithelial plasticity and TGF-β1-induced loss of epithelial cell integrity.
abstract: Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine and critically involved in the progression of a variety of cancers. TGF-β1 signaling can impair tumor development by its anti-proliferative and pro-apoptotic features. In contrast, it may actively promote tumor progression and cancer cell dissemination by inducing a gradual switch from epithelial towards mesenchymal-like cell features (EMT-like), including decreased intercellular adhesion. Here, we show that expression of the transcription factor Basonuclin-1 (Bnc1) modulates TGF-β1-induced epithelial dedifferentiation of mammary epithelial cells. RNAi-mediated repression of Bnc1 resulted in enhanced intercellular adhesion and strongly impaired TGF-β1-dependent sheet disintegration and cell scattering. In contrast, forced expression of Bnc1 modifies plasma membrane/cytoskeletal dynamics and seemingly interferes with the initiation of sustainable cell-cell contacts. Follow-up analyses revealed that Bnc1 affects the expression of numerous TGF-β1-responsive genes including distinct EMT-related transcription factors, some of which modulate the expression of Bnc1 themselves. These results suggest that Bnc1 is part of a transcription factor network related to epithelial plasticity with reciprocal feedback-loop connections on which Smad-factors integrate TGF-β1 signaling. Our study demonstrates that Bnc1 regulates epithelial plasticity of mammary epithelial cells and influences outcome of TGF-β1 signaling.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Feuerborn
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Mathow
authors.affiliation: Physiological Genomics and Medicine, MRC Clinical Sciences, Imperial College, London, UK.
authors.forename: P K
authors.initials: PK
authors.lastname: Srivastava
authors.affiliation: Department of Medical Research, Faculty of Medicine, Medical Research Centre (ZMF), University of Heidelberg, Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D054337:Cell Dedifferentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C077914:BNC1 protein, human