title: Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
abstract: Understanding the mechanisms of cancer initiation will help to prevent and manage the disease. At present, the role of the breast microenvironment in transformation remains unknown. As BMP2 and BMP4 are important regulators of stem cells and their niches in many tissues, we investigated their function in early phases of breast cancer. BMP2 production by tumor microenvironment appeared to be specifically upregulated in luminal tumors. Chronic exposure of immature human mammary epithelial cells to high BMP2 levels initiated transformation toward a luminal tumor-like phenotype, mediated by the receptor BMPR1B. Under physiological conditions, BMP2 controlled the maintenance and differentiation of early luminal progenitors, while BMP4 acted on stem cells/myoepithelial progenitors. Our data also suggest that microenvironment-induced overexpression of BMP2 may result from carcinogenic exposure. We reveal a role for BMP2 and the breast microenvironment in the initiation of stem cell transformation, thus providing insight into the etiology of luminal breast cancer.
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Chapellier
authors.affiliation: Inserm U916, Institut Bergonié, University of Bordeaux, 33076 Bordeaux, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bachelard-Cascales
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Xenia
authors.initials: X
authors.lastname: Schmidt
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Clément
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France; Centre Léon Bérard, 69000 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France; Centre Léon Bérard, 69000 Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Delay
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Jammot
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France; Centre Léon Bérard, 69000 Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Pochon
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Besançon
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Voeltzel
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Caron de Fromentel
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France; Centre Léon Bérard, 69000 Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France; Centre Léon Bérard, 69000 Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: Inserm U916, Institut Bergonié, University of Bordeaux, 33076 Bordeaux, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Iggo
authors.affiliation: CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France; Université de Lyon, 69000 Lyon, France; Department of Immunity, Virus, and Microenvironment, 69000 Lyon, France; Université de Lyon 1, ISPB, 69000 Lyon, France. Electronic address: veronique.maguer-satta@lyon.unicancer.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Maguer-Satta
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002273:Carcinogens; D052005:Bone Morphogenetic Protein Receptors, Type I