Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells

Shawn Pan; Chaoshen Yuan; Abderrahmane Tagmount; Ruthann A Rudel; Janet M Ackerman; Paul Yaswen; Chris D Vulpe; Dale C Leitman

doi:10.1289/ehp.1409200

Lifestyle and Environment · Environmental Exposures

Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells

Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC

Published May 2016 Environmental Health Perspectives

DOI 10.1289/ehp.1409200 PMID 26502914 PMC PMC4858398

RRM Academy Synopsis

In vitro, heregulin let less butylparaben stimulate breast cancer cells

A 2016 laboratory study of human breast cancer cell lines found that the growth factor heregulin lowered the butylparaben dose that stimulated cell growth. Butylparaben is a preservative in many cosmetics. The effect depended on estrogen receptor alpha (ERα). In BT-474 cells, drugs that block ERα prevented the synergistic rise in c-Myc, an oncogene.

Key Findings

Among four parabens, propylparaben and butylparaben raised c-Myc mRNA most without heregulin (HRG). Butylparaben raised it most with and without HRG. HRG alone produced an approximately 3-fold increase.
Butylparaben with HRG synergistically raised c-Myc protein in BT-474 and MCF-7 cells. SKBR3 cells, which lack ERα, showed no synergy. ICI 182,780, raloxifene and tamoxifen blocked the synergistic rise in BT-474 cells.
HRG lowered the butylparaben dose needed to raise c-Myc mRNA. In the five-day cell count, HRG lowered the smallest butylparaben dose that significantly increased cell number.
HRG raised ERα phosphorylation at serine 167 from 30 minutes, maximal at 2 hours. With butylparaben and HRG, ERα binding to the c-Myc enhancer peaked at 8-fold at 1 hour.

Interpretation

This laboratory study tested these effects in human breast cancer cell lines, mainly BT-474 cells. The authors report that the concentrations producing effects with HRG fall within the range previously reported in human breast tissue. The findings support further study of these effects in normal human breast cells and in tumors.

RRM Context

Restorative reproductive medicine studies the signals that control hormones in women and men. Exposures from the environment are part of that picture. In cultured breast cancer cells, a cosmetic ingredient that mimics estrogen acted at lower doses when a second signal was active. The authors suggest testing other estrogen mimics alongside HER ligands.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

Xenoestrogens are synthetic compounds that mimic endogenous estrogens by binding to and activating estrogen receptors. Exposure to estrogens and to some xenoestrogens has been associated with cell proliferation and an increased risk of breast cancer. Despite evidence of estrogenicity, parabens are among the most widely used xenoestrogens in cosmetics and personal-care products and are generally considered safe. However, previous cell-based studies with parabens do not take into account the signaling cross-talk between estrogen receptor α (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 polymerase chain reaction, 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 with the effects of 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 results show that HER ligands enhanced 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.

CITATION: Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. 2016. Parabens and human epidermal growth factor receptor ligand cross-talk in breast cancer cells. Environ Health Perspect 124:563-569; http://dx.doi.org/10.1289/ehp.1409200.

Topics

Lifestyle and Environment › Environmental Exposures › Personal Care and Household Products · General Gynecology › Breast Health › Breast Cancer Risk

Shawn Pan, Chaoshen Yuan, Abderrahmane Tagmount, Ruthann A Rudel, Janet M Ackerman, Paul Yaswen, Chris D Vulpe, Dale C Leitman

S Pan, C Yuan, A Tagmount, R Rudel, J Ackerman, P Yaswen, Christine Vulpe, Christopher Vulpe, C Vulpe, D Leitman

PMID 26502914 26502914 DOI 10.1289/ehp.1409200 10.1289/ehp.1409200 Pan et al. 2016, Pan 2016

Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells

In vitro, heregulin let less butylparaben stimulate breast cancer cells

Key Findings

Interpretation

RRM Context

Abstract

Topics

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