Long chain alkylphenol mixture promotes breast cancer initiation and progression through an ER36-mediated mechanism

Clémence Chamard-Jovenin 1 Amand Chesnel 1 Chloé Morel 1 Emmanuel Bresso 2 Marie-Dominique Devignes 3, 2 Malika Smaïl-Tabbone 2 Taha Boukobza 1 Hélène Dumond 1
2 ORPAILLEUR - Knowledge representation, reasonning
Inria Nancy - Grand Est, LORIA - NLPKD - Department of Natural Language Processing & Knowledge Discovery
3 CAPSID - Computational Algorithms for Protein Structures and Interactions
Inria Nancy - Grand Est, LORIA - AIS - Department of Complex Systems, Artificial Intelligence & Robotics
Résumé : Growing source of evidence suggests that exposure to estrogen mimicking agents is a risk factor for breast cancer onset and progression. Long chain alkylphenols are man-made compounds still present in household products, industrial and agricultural processes, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. Recently, we have demonstrated that a realistic mixture of 4-tert-octylphenol and 4-nonylphenol can stimulate proliferation and modulate epigenetic status of testicular cancer germ cells through a rapid, Estrogen Receptor alpha 36 (ER)- dependent non genomic pathway. Since high ERα36 expression enhances expression of migration/invasion markers in breast tumors, we addressed the question of its involvement in response to alkylphenol exposure in MCF10A mammary epithelial cell lineand MCF7 estrogen-sensitive cancer cells. ERα36 overexpression or gene-silencing strategies combined to microarray analyses of the mixture target genes were used in MCF10A and MCF7 cells in order to characterize the molecular phenotype of exposed cells. A customized database was designed to analyze comprehensive gene expression results, nonlinear correlation analyses, and mutual information computations helpful for the modeling of alkylphenol/ERα36-dependent pathways. Our results highlight a key role for ER in alkylphenol non genomic src protein kinase /PI3-kinase/serine-threonine kinase Akt/ nuclear factor-kappa B signaling in non cancerous epithelial breast cells. Hence, alkylphenol and/or ER-dependent control of the proliferation, adhesion and survival pathway opens the way for understanding the link between endocrine disruptor exposure and the burden of hormone sensitive cancers.
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Conference papers
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Submitted on : Tuesday, May 24, 2016 - 12:10:57 PM
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Clémence Chamard-Jovenin, Amand Chesnel, Chloé Morel, Emmanuel Bresso, Marie-Dominique Devignes, et al.. Long chain alkylphenol mixture promotes breast cancer initiation and progression through an ER36-mediated mechanism. 4ème Colloque Inter-Régional Grand-Est de Recherche Translationnelle en Oncologie, Oncotrans 2015, Jun 2015, Dijon, France. ⟨hal-01320699⟩

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