| Abstract: | Data concerning possible carcinogenic action of polybrominated diphenyl ethers (PBDEs) in hormone‐dependent tissues are limited. Our earlier studies showed that 2,2′,4,4′‐tetrabromodiphenyl ether (BDE‐47) stimulated OVCAR‐3 and MCF‐7 cell proliferation, while its hydroxylated metabolites (5‐OH‐BDE‐47 and 6‐OH‐BDE‐47) increased estrogen receptors protein expression and extracellular signal‐regulated kinase 1/2 and protein kinase Cα phosphorylation in these cell lines. In addition to cell proliferative disorder, a failure in the regulation of apoptosis can also lead to the formation and development of tumors. Therefore, in the present study, we investigated the effect of BDE‐47 and its metabolites (2.5–50 ng ml–1) on the expression of apoptosis regulatory genes and proteins, caspase‐8 and ‐9 activity and DNA fragmentation induced by extracellular signal‐regulated kinase inhibitor (PD098059) and protein kinase Cα inhibitor (Gӧ 6976) in ovarian (OVCAR‐3) and breast (MCF‐7) cancer cells. In OVCAR‐3 cells, BDE‐47 upregulated expression of most of the investigated genes and increased protein expression of tumor necrosis factor (TNF)‐α, TNF receptor 1, caspase‐6, Bcl‐xl and caspase‐8 activity. Whereas in MCF‐7 cells, BDE‐47 resulted in the downregulation of most of the investigated genes, and decreased caspase‐8 and ‐9 activity. In both OVCAR‐3 and MCF‐7 cells, the expression of most of the investigated genes were downregulated by metabolites. Exposure of OVCAR‐3 cells to 5‐OH‐BDE‐47 corresponded with a decrease in the protein expression of caspase‐6, caspase‐9 and Bcl‐xl and treatment with 6‐OH‐BDE‐47 decreased Bcl‐xl and TNF receptor 1 expression in OVCAR‐3 cells and caspase‐9 expression in MCF‐7 cells. Hydroxylated metabolites of BDE‐47 have strong inhibitory effects on apoptosis in ovarian and breast tumor cells and thus should be considered potential carcinogens in hormone‐dependent cancers. Copyright © 2016 John Wiley & Sons, Ltd. |
