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 e...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2017-03, Vol.38 (3), p.252
Main Authors: Sauer, Scott J, Tarpley, Michael, Shah, Imran, Save, Akshay V, Lyerly, H Kim, Patierno, Steven R, Williams, Kevin P, Devi, Gayathri R
Format: Article
Language:English
Subjects:
Benzhydryl Compounds - pharmacology
Benzhydryl Compounds - toxicity
Carcinogens, Environmental - pharmacology
Carcinogens, Environmental - toxicity
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Resistance, Neoplasm - genetics
Estrogen Receptor alpha - genetics
Extracellular Signal-Regulated MAP Kinases - genetics
Female
Humans
Inflammatory Breast Neoplasms - drug therapy
Inflammatory Breast Neoplasms - genetics
Inflammatory Breast Neoplasms - pathology
Original Manuscript
Oxidative Stress - drug effects
Phenols - pharmacology
Phenols - toxicity
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Signal Transduction - drug effects
Spheroids, Cellular - drug effects
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Summary: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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgx003