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Title: A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling

Abstract

Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR +/+ and AhR −/− models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05 μM HCB induced cell migration and TGF-β1 signaling, whereas 5 μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5 μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR +/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3 mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR +/+ mice. Primary culture of mammary epithelial cells from AhR +/+ micemore » showed reduced AhR mRNA levels after HCB exposure (0.05 and 5 μM). Interestingly, AhR −/− mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds. - Highlights: • 0.05 μM HCB induces migration and TGF-β1 signaling in mammary epithelial cells NMuMG. • 5 μM HCB reduces migration, and promotes cell cycle arrest and AhR nuclear pathway in NMuMG. • HCB enhances α-SMA and decreases TGF-β receptor II expression in fibroblasts AhR +/+. • Conditioned medium from fibroblasts AhR +/+ exposed to HCB enhances NMuMG migration. • HCB increases hyperplasia and branching morphogenesis in AhR +/+ mice mammary gland.« less

Authors:
 [1];  [2];  [1];  [3];  [2];
  1. Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, 5° piso, CP1121, Buenos Aires (Argentina)
  2. Universidad de Extremadura, Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular y Genética, Laboratorio de Biología Molecular del Cáncer, Avenida de Elvas s/n, CP06080 Badajoz (Spain)
  3. Universidad de Buenos Aires, Facultad de Medicina, Departamento de Ciencias Fisiológicas, Sección Patología, Laboratorio de Fisiopatogenia, Paraguay 2155, 7° piso, CP1121, Buenos Aires (Argentina)
Publication Date:
OSTI Identifier:
22722953
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 334; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AROMATICS; BRANCHING RATIO; CELL CYCLE; CELL PROLIFERATION; DIOXIN; FIBROBLASTS; GROWTH FACTORS; MAMMARY GLANDS; MICE; MIGRATION; MORPHOGENESIS; PLANT GROWTH; RECEPTORS; SIGNALS

Citation Formats

Miret, Noelia, Rico-Leo, Eva, Pontillo, Carolina, Zotta, Elsa, Fernández-Salguero, Pedro, and others, and. A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.09.012.
Miret, Noelia, Rico-Leo, Eva, Pontillo, Carolina, Zotta, Elsa, Fernández-Salguero, Pedro, & others, and. A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling. United States. doi:10.1016/J.TAAP.2017.09.012.
Miret, Noelia, Rico-Leo, Eva, Pontillo, Carolina, Zotta, Elsa, Fernández-Salguero, Pedro, and others, and. Wed . "A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling". United States. doi:10.1016/J.TAAP.2017.09.012.
@article{osti_22722953,
title = {A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling},
author = {Miret, Noelia and Rico-Leo, Eva and Pontillo, Carolina and Zotta, Elsa and Fernández-Salguero, Pedro and others, and},
abstractNote = {Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR +/+ and AhR −/− models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05 μM HCB induced cell migration and TGF-β1 signaling, whereas 5 μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5 μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR +/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3 mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR +/+ mice. Primary culture of mammary epithelial cells from AhR +/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5 μM). Interestingly, AhR −/− mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds. - Highlights: • 0.05 μM HCB induces migration and TGF-β1 signaling in mammary epithelial cells NMuMG. • 5 μM HCB reduces migration, and promotes cell cycle arrest and AhR nuclear pathway in NMuMG. • HCB enhances α-SMA and decreases TGF-β receptor II expression in fibroblasts AhR +/+. • Conditioned medium from fibroblasts AhR +/+ exposed to HCB enhances NMuMG migration. • HCB increases hyperplasia and branching morphogenesis in AhR +/+ mice mammary gland.},
doi = {10.1016/J.TAAP.2017.09.012},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 334,
place = {United States},
year = {2017},
month = {11}
}