title: Long-term exposure to bisphenol A or benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signaling.
abstract: Bone morphogenetic protein 2 (BMP2) and BMP4 are key regulators of the fate and differentiation of human mammary epithelial stem cells (SCs), as well as of their niches, and are involved in breast cancer development. We established that MCF10A immature mammary epithelial cells reliably reproduce the BMP response that we previously identified in human primary epithelial SCs. In this model, we observed that BMP2 promotes luminal progenitor commitment and expansion, whereas BMP4 prevents lineage differentiation. Environmental pollutants are known to promote cancer development, possibly by providing cells with stem-like features and by modifying their niches. Bisphenols, in particular, were shown to increase the risk of developing breast cancer. Here, we demonstrate that chronic exposure to low doses of bisphenol A (BPA) or benzo(a)pyrene (B(a)P) alone has little effect on SCs properties of MCF10A cells. Conversely, we show that this exposure affects the response of immature epithelial cells to BMP2 and BMP4. Furthermore, the modifications triggered in MCF10A cells on exposure to pollutants appeared to be predominantly mediated by altering the expression and localization of type-1 receptors and by pre-activating BMP signaling, through the phosphorylation of small mothers against decapentaplegic 1/5/8 (SMAD1/5/8). By analyzing stem and progenitor properties, we reveal that BPA prevents the maintenance of SC features prompted by BMP4, whereas promoting cell differentiation towards a myoepithelial phenotype. Inversely, B(a)P prevents BMP2-mediated luminal progenitor commitment and expansion, leading to the retention of stem-like properties. Overall, our data indicate that BPA and B(a)P distinctly alter the fate and differentiation potential of mammary epithelial SCs by modulating BMP signaling.
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Tumor Escape Signaling, Centre Léon Bérard, Lyon, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Clément
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Tumor Escape Signaling, Centre Léon Bérard, Lyon, France.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Xu
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer and Environnement, Centre Léon Bérard, Lyon, France.
authors.forename: Caterina F
authors.initials: CF
authors.lastname: Donini
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Tumor Escape Signaling, Centre Léon Bérard, Lyon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Clément
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer Cell Plasticity, Centre Léon Bérard, Lyon, France.
authors.forename: Soleilmane
authors.initials: S
authors.lastname: Omarjee
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Tumor Escape Signaling, Centre Léon Bérard, Lyon, France.|Centre Léon Bérard, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Delay
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer Cell Plasticity, Centre Léon Bérard, Lyon, France.|Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer and Environnement, Centre Léon Bérard, Lyon, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Fervers
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer Cell Plasticity, Centre Léon Bérard, Lyon, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Le Romancer
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Cancer and Environnement, Centre Léon Bérard, Lyon, France.
authors.forename: Pascale A
authors.initials: PA
authors.lastname: Cohen
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Lyon, F-69008, France.|Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon Cedex 08, F-69008, France.|Department of Tumor Escape Signaling, Centre Léon Bérard, Lyon, France.|CNRS GDR 3697 Micronit, Tours, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Maguer-Satta
mesh_terms: D001559:Benzhydryl Compounds / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D010636:Phenols / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001564:Benzo(a)pyrene; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D004785:Environmental Pollutants; D010636:Phenols; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C006780:bisphenol A; D000098826:Bisphenol A Compounds