Bisphenol a Interacts with Gper, Activates EGFR and ERK Signaling and Antagonizes Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Breast Cancer Cells

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: SUN 0345-0362-Growth Factor/ Tyrosine Kinase signaling, Inhibin/Activin Superfamily, Cell Regulation
Basic
Sunday, June 22, 2014: 1:00 PM-3:00 PM
Hall F (McCormick Place West Building)

Poster Board SUN-0345
Scott Jeffrey Sauer, PhD1, John B Davis2, H Kim Lyerly, MD3, Imran Shah, PhD4, Kevin P Williams, PhD5 and Gayathri R Devi, PHD6
1Duke Univ Med Ctr, Durham, NC, 2Duke University, 3Duke University Medical Center, 4Environmental Protection Agency, 5North Carolina Central University, 6Duke University Med Ctr, Durham, NC
Bisphenol A (BPA), a known endocrine disrupting agent and ubiquitously found plasticizer has recently been identified to interact with G-protein-coupled receptor 30 (GPR30/GPER), an alternate estrogen receptor (ER). GPER overexpression has been observed in breast cancer with particularly high levels in an aggressive and commonly hormone-independent subtype, inflammatory breast cancer (IBC). In the current study, screening the EPA Tox Cast I library of environmental chemicals using a high-throughput cell proliferation assay identified  BPA to be one of the top toxicants that increased proliferation in IBC cells, irrespective of ER status.  This is supported by recent evidence that BPA can induce proliferative effects in ER-negative breast cancer cells via GPER. Further, GPER has the ability to activate downstream ERK signaling via cross-talk with the epidermal growth factor receptor (EGFR) pathway. Therefore, we sought to determine BPA’s effect on the anticancer efficacy of EGFR tyrosine kinase inhibitors (TKIs) used clinically for the treatment of breast cancer. Using normal and breast cancer cells with differential expression of ERa, GPER and EGFR, proliferation was measured using an MTT assay to assess the effect of BPA alone and in combination with EGFR TKIs lapatinib and gefitinib. Clonogenic, anchorage-independent growth, Annexin-V/7-AAD flow cytometry and signaling assays were also used to assess the functional effect of BPA on lapatinib action. Our results reveal that breast cancer cells with either EGFR-activation or ER-positivity were highly responsive to BPA-mediated proliferative effects. BPA increased pEGFR and pERK levels along with expression of antioxidants (SOD1/2, GSTP1) in EGFR-activated breast cancer cells. Further, we observed that lapatinib in addition to inhibiting pEGFR levels decreased GPER expression. BPA attenuated the cancer cell growth inhibitory effect of EGFR-TKIs and abrogated the lapatinib-mediated inhibition of pEGFR, GPER and downstream pNFkB signaling. In conclusion, understanding BPA’s effect on drug resistance is a new paradigm that has immediate implications in treatment regimens.

Nothing to Disclose: SJS, JBD, HKL, IS, KPW, GRD

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: Duke Cancer Institute - Cancer and Environment Initiative P3917733 sub-award (GRD); Department of Surgery Bolognesi award (GRD); American Cancer Society RSG-08-290-01-CCE (GRD); National Cancer Institute training grant T32CA009111 (SJS); JD (Duke URS Independent Study)
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