Common preservative may increase breast cancer

Estrogen-mimicing chemicals called parabens commonly found in an array of personal care products, may be more dangerous at lower doses than previously thought. Parabens are preservatives used in shampoos, commercial moisturizers, shaving gels, personal lubricants, topical pharmaceuticals, spray tanning solution, makeup and toothpaste. They are also used as food additives.

Findings published October 27 in Environmental Health Perspectives, could have implications for the development of breast cancer and other diseases influenced by estrogens. The study also raises questions about current safety testing methods. These methods may not predict the true potency of parabens and their effects on human health.

Parabens are a class of preservatives widely-used in consumer products like shampoos, cosmetics, body lotions and sunscreens. The chemicals activate the same estrogen receptor as the natural hormone estradiol.

Studies have linked exposure to estradiol and related estrogens to increased risk of breast cancer and reproductive problems. As a result, the use of parabens in consumer products increasingly is a public health concern.

How much parabens might contribute to breast cancer risk is unclear.

"Although parabens are known to mimic the growth effects of estrogens on breast cancer cells, some consider their effect too weak to cause harm. But this might not be true when parabens are combined with other agents that regulate cell growth."

Dale Leitman MD PhD, lead investigator, gynecologist and molecular biologist in the Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA

Existing chemical safety tests, which measure the effects of chemicals on human cells, look only at parabens in isolation. They fail to account for parabens interaction with other types of signaling molecules that increase breast cancer risk.

"Scientists and regulators are using potency estimates from these kinds of tests and are assuming they are relevant to what goes on in real life. But if you don't design the right test, you can be off by a lot," says co-author Ruthann Rudel, a toxicologist at Silent Spring Institute.

To better reflect real life, researchers looked at breast cancer cells expressing two types of receptors: estrogen receptors and HER2.

Approximately 25 percent of breast cancers produce an abundance of HER2, or human epidermal growth factor receptor 2. HER2-positive tumors tend to grow and spread more aggressively than other types of breast cancer.

Researchers activated HER2 receptors in breast cancer cells with a growth factor called heregulin — naturally made in breast cells — while exposing the breast cancer cells to parabens.

The effect was significant. Not only did parabens trigger the cells to proliferate, in HER2-activated cells parabens were able to stimulate breast cancer cell growth even at concentrations 100 times lower than cells deprived of heregulin.

This demonstrates parabens may be more potent at lower doses than previous studies suggested.

Regulators may need to rethink the potential impacts of parabens on the development of breast cancer, particularly on HER2 and estrogen receptor positive breast cells.

"While this study focused on parabens, it's also possible that the potency of other estrogen mimics have been underestimated by current testing," says co-author Chris Vulpe PhD, a toxicologist formerly with the Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, USA, who is now at the Center for Environmental and Human Toxicology at the University of Florida College of Veterinary Medicine, USA.

Since people come into contact with multiple chemicals every day through consumer products — understanding how mixes of hormone-mimicing chemicals affect growth factors promoting cell growth, might better reflect a person's potential cancer exposure risk.

Of increasing concern is how exposure to multiple chemicals during critical periods of development including puberty and pregnancy increases a person's susceptibility to breast cancer later in life.

Abstract
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.

Additional background: Shawn Pan, Chaoshen Yuan, Abderrahmane Tagmount, Ruthann A. Rudel, Janet M. Ackerman, Paul Yaswen, Chris D. Vulpe, and Dale C. Leitman. 2015. Parabens and Human Epidermal Growth Factor Receptor Ligands Cross-Talk in Breast Cancer Cells. Environmental Health Perspectives.

Link to paper: http://ehp.niehs.nih.gov/14-09200

The California Breast Cancer Research Program helped fund this research.

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