Bisphenol A activates EGFR and ERK promoting proliferation, tumor spheroid formation and resistance to EGFR pathway inhibition in estrogen receptor-negative inflammatory breast cancer cells


Emerging evidence from epidemiological studies suggests a link between environmental chemical exposure and progression of aggressive breast cancer subtypes. Of all clinically distinct types of breast cancers, the most lethal phenotypic variant is inflammatory breast cancer (IBC). Overexpression of epidermal growth factor receptors (EGFR/HER2) along with estrogen receptor (ER) negativity is common in IBC tumor cells, which instead of a solid mass present as rapidly proliferating diffuse tumor cell clusters. Our previous studies have demonstrated a role of an adaptive response of increased antioxidants in acquired resistance to EGFR-targeting drugs in IBC. Environmental chemicals are known to induce oxidative stress resulting in perturbations in signal transduction pathways. It is therefore of interest to identify chemicals that can potentiate EGFR mitogenic effects in IBC. Herein, we assessed in ER-negative IBC cells a subset of chemicals from the EPA ToxCast set for their effect on EGFR activation and in multiple cancer phenotypic assays. We demonstrated that endocrine-disrupting chemicals such as bisphenol A (BPA) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane can increase EGFR/ERK signaling. BPA also caused a corresponding increase in expression of SOD1 and anti-apoptotic Bcl-2, key markers of antioxidant and anti-apoptotic processes. BPA potentiated clonogenic growth and tumor spheroid formation in vitro, reflecting IBC-specific pathological characteristics. Furthermore, we identified that BPA was able to attenuate the inhibitory effect of an EGFR targeted drug in a longer-term anchorage-independent growth assay. These findings provide a potential mechanistic basis for environmental chemicals such as BPA in potentiating a hyperproliferative and death-resistant phenotype in cancer cells by activating mitogenic pathways to which the tumor cells are addicted for survival.


2005: bisphenol A in dental fillings


A chemical found in plastics may put women exposed to it at greater risk of developing breast cancer, it seems. A study in mice has found that minute doses of the oestrogen-like substance increase breast tissue development, and higher density breast tissue is a risk factor for cancer.

Many hard plastics contain the compound bisphenol A, which can leach into food after heating. The chemical also appears in some dental fillings and the linings of tin cans. Industry began using bisphenol A in the 1950s, but in recent years scientists have documented how it mimics the hormone oestrogen.

Some scientists worry that because oestrogen plays such a crucial role in the development of a fetus’s reproductive system and other organs, exposure to bisphenol A in the womb could cause problems. A recent study of mice exposed in this way found that the artificial compound caused abnormally high levels of growth in the male animals’ prostate glands1.

Now, another team of researchers has investigated the effects of this chemical on female mice: the results are reported in the journal Endocrinology2.