title: Differential effects of a complex organochlorine mixture on the proliferation of breast cancer cell lines.
abstract: Organochlorine compounds (OCs) are a group of persistent chemicals that accumulate in fatty tissues with age. Although OCs has been tested individually for their capacity to induce breast cancer cell proliferation, few studies examined the effect of complex mixtures that comprise compounds frequently detected in the serum of women. We constituted such an OC mixture containing 15 different components in environmentally relevant proportions and assessed its proliferative effects in four breast cancer cell lines (MCF-7, T47D, CAMA-1, MDAMB231) and in non-cancerous CV-1 cells. We also determined the capacity of the mixture to modulate cell cycle stage of breast cancer cells and to induce estrogenic and antiandrogenic effects using gene reporter assays. We observed that low concentrations of the mixture (100 × 10(3) and 50 × 10(3) dilutions) stimulated the proliferation of MCF-7 cells while higher concentrations (10 × 10(3) and 5 × 10(3) dilutions) had the opposite effect. In contrast, the mixture inhibited the proliferation of non-hormone-dependent cell lines. The mixture significantly increased the number of MCF-7 cells entering the S phase, an effect that was blocked by the antiestrogen ICI 182,780. Low concentrations of the mixture also caused an increase in CAMA-1 cell proliferation but only in the presence estradiol and dihydrotestosterone (p<0.05 at the 50 × 10(3) dilution). DDT analogs and polychlorinated biphenyls all had the capacity to stimulate the proliferation of CAMA-1 cells in the presence of sex steroids. Reporter gene assays further revealed that the mixture and several of its constituents (DDT analogs, aldrin, dieldrin, β-hexachlorocyclohexane, toxaphene) induced estrogenic effects, whereas the mixture and several components (DDT analogs, aldrin, dieldrin and PCBs) inhibited the androgen signaling pathway. Our results indicate that the complex OC mixture increases the proliferation of MCF-7 cells due to its estrogenic potential. The proliferative effect of the mixture on CAMA-1 cells in the presence of sex steroids appears mostly due to the antiandrogenic properties of p,p'-DDE, a major constituent of the mixture. Other mixtures of contaminants that include emerging compounds of interest such as brominated flame retardants and perfluoroalkyl compounds should be tested for their capacity to induce breast cancer cell proliferation.
authors.affiliation: Axe de recherche en santé des populations et environnementale, Centre de recherche du Centre hospitalier universitaire de Québec and Université Laval, 2875 Boulevard Laurier, Édifice Delta 2, bureau 600, Québec, QC, Canada. 4aubem@videotron.ca
authors.forename: Michel
authors.initials: M
authors.lastname: Aubé
authors.forename: Christian
authors.initials: C
authors.lastname: Larochelle
authors.forename: Pierre
authors.initials: P
authors.lastname: Ayotte
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006843:Hydrocarbons, Chlorinated; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D000077267:Fulvestrant; D004958:Estradiol