title: Simvastatin down-regulates differential genetic profiles produced by organochlorine mixtures in primary breast cell (HMEC).
abstract: Women all over the world are exposed to an unavoidable contamination by organochlorine pesticides and other chemical pollutants. Many of them are considered as xenoestrogens and have been associated with the development and progression of breast cancer. We have demonstrated that the most prevalent pesticide mixtures found in healthy women and in women diagnosed with breast cancer modulates the gene expression in human epithelial mammary cells. Statins are well-known cholesterol-depleting agents acting as inhibitors of cholesterol synthesis. Since the early 1990s, it has been known that statins could be successfully used in cancer therapy, including breast cancer, but the exact mechanism behind anti-tumor activity of the statins remains unclear. In the present study we evaluated the effect of simvastatin in the gene expression pattern induced by realistic organochlorine mixtures found in breast cancer patients. The gene expression of 94 genes related with the cell signaling pathways were assessed. Our results indicate that simvastatin exerts a global down regulating effect on successfully determined genes (78.7%), thus attenuating the effects induced by organochlorine mixtures on the gene profile of human mammary epithelial cells. This effect was more evident on genes whose function is the ATP-binding process (that also were particularly up-regulated by pesticide mixtures). We also found that MERTK (a proto-oncogene which is overexpressed in several malignancies) and PDGFRB (a member of the platelet-derived growth factor family whose expression is high in breast-cancer cells that have become resistant to endocrine therapy) were among the genes with a higher differential regulation by simvastatin. Since resistance to treatment with tyrosine kinase inhibitors is closely related to MERKT, our findings would enhance the possible utility of statins in breast cancer treatment, i.e. improving therapeutic results combining statins with tyrosine Kinase inhibitors.
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rivero
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Luis Alberto
authors.initials: LA
authors.lastname: Henríquez-Hernández
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: D Boada
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Pestano
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: P Luzardo
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Camacho
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Zumbado
authors.affiliation: Research Group in Environment and Health, Research Institute of Biomedical and Health Sciences (IUIBS), Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigación del Cáncer (ICIC), Faculty of Health Sciences, Paseo Blas rera Felipe s/n, 35016 Las Palmas de Gran Canaria, Spain. Electronic address: pilarfdez.valeron@ulpgc.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: F Valerón
mesh_terms: D002460:Cell Line; D052244:Endocrine Disruptors / Q000633:toxicity*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects*; D010575:Pesticides / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019821:Simvastatin / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D006843:Hydrocarbons, Chlorinated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000715470:MAS1 protein, human; D010575:Pesticides; D000090063:Proto-Oncogene Mas; D019821:Simvastatin; D011505:Protein-Tyrosine Kinases; D054460:rho-Associated Kinases