Parabens and Human Epidermal Growth Factor Receptor Ligands Cross-Talk in Breast Cancer Cells.
Environ Health Perspect. 2015 Oct 27. Epub 2015 Oct 27. PMID: 26502914
BACKGROUND: Xenoestrogens are synthetic compounds that mimic endogenous estrogens by binding to and activating estrogen receptors. Exposure to estrogens and some xenoestrogens has been associated with cell proliferation and increased risk of breast cancer. Despite evidence of estrogenicity, parabens are among the most widely used xenoestrogens in cosmetics and personal care products, and generally considered safe. However, previous cell based studies with parabens do not take into account the signaling cross-talk between estrogen receptor (ERα) and the human epidermal growth factor receptor (HER) family.
OBJECTIVES: We investigated the hypothesis that the potency of parabens can be increased with HER ligands, such as heregulin (HRG).
METHODS: The effects of HER ligands on paraben activation of c-Myc expression and cell proliferation were determined by real-time PCR, western blots, flow cytometry and chromatin immunoprecipitation assays in ERα- and HER2-positive human BT-474 breast cancer cells.
RESULTS: Butylparaben (BP) and HRG produced a synergistic increase in c-Myc mRNA and protein levels in BT-474 cells. Estrogen receptor antagonists blocked the synergistic increase in c-Myc protein levels. The combination of BP and HRG also stimulated proliferation of BT-474 cells compared to BP alone. HRG decreased the dose required for BP-mediated stimulation of c-Myc mRNA expression and cell proliferation. HRG caused the phosphorylation of serine 167 in ERα. BP and HRG produced a synergistic increase in ERα recruitment to the c-Myc gene.
CONCLUSION: Our studies demonstrate that HER ligands enhance the potency of BP to stimulate oncogene expression and breast cancer cell proliferation in vitro via ERα, suggesting that parabens might be active at exposure levels not previously considered toxicologically relevant from studies testing their effects in isolation.