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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
Citation:
Sauer, S., M. Tarpley, I. Shah, A. Save, H. Lyerly, S. Patierno, K. Williams, AND G. Devi. 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. CARCINOGENESIS. Oxford University Press, Cary, NC, 38(3):252–260, (2017).
Impact/Purpose:
• Agency Research Drivers - Inflammatory breast cancer (IBC) is a distinct form of breast cancer, with a rapid rate of progression and acquired therapeutic resistance. IBC is the deadliest breast cancer variant. • Science Challenge – Studies suggest that exposure to chemicals in the environment can affect clinical outcomes of advanced cancers like IBC. The present study tested the hypothesis that environmental chemicals promote cancer cell proliferation. • Research Approach – We screened 309 environmental chemicals, including 31 food-related and agricultural chemicals, for effects on IBC cells. • Results – The effects of these chemicals were evaluated in IBC cells using tests for measuring: nuclear count, cell viability, cell proliferation, cell growth signaling, and increased cell colony formation and growth. Two chemicals were positive in all tests. • Anticipated Impact/Expected use – These studies demonstrate the utility of a systematic tiered-testing approach to identify environmental chemicals that enhance cancers like IBC.
Description:
Background: Inflammatory breast cancer (IBC) is a distinct and the deadliest breast cancer variant, which shows a rapid rate of progression and acquired therapeutic resistance. Epidemiological studies suggest that chemical exposure in the environment and consumer products can affect clinical outcomes of advanced cancers like IBC. The present study tested the hypothesis that environmental chemicals promote cancer cell proliferation by enhancing EGFR/ERK mitogenic signaling. Methods and Results: We prioritized 309 environmental chemicals available from the EPA ToxCast Phase I program using IBC-relevant in vitro assays. This analysis identified 31 food-related and agricultural chemicals that exhibited activity at doses <10 μM. The concentration-dependent (39 nM-20 μM) effects of these chemicals were evaluated in IBC cells using tiered tests for measuring: nuclear count, cell viability, cell proliferation, mitogenic (ERK and EGFR) signaling, and increased cell colony formation and growth. Only BPA and HPTE were positive in all tests. Interestingly, BPA also reversed the growth inhibitory and signaling effects of a targeted EGFR tyrosine kinase inhibitor.Conclusion: These studies demonstrate the utility of a systematic tiered-testing approach to identify environmental chemicals that enhance a hyperproliferative phenotype of cancers like IBC with a short latency period.
