P2-03-06: Endothelin-1/Endothelin A Receptor Signalling in Breast Cancer.

Background: Endothelin-1 (ET-1) and endothelin A receptor (ETAR) are implicated in breast cancer growth and progression. ET-1 is secreted by both tumor cells and stroma (macrophages, endothelial cells). The purpose of this study is to evaluate ET-1/ETAR role on cell proliferation and its effects on EGFR signaling pathway. Materials and Methods: Two breast cancer cell lines: MCF-7 and MDA-MB-231 were stimulated with ET-1. Proliferation of breast cancer cells was analyzed using MTT assay. Protein expression (EGFR, pEGFR, AKT, pAKT, ERK, pERK) was evaluated by Western blot. siRNA knockdown of endothelin A receptor (ETAR) was performed in MCF-7 and MDA-MB-231. Results: ET-1 stimulated proliferation in both cell lines. Interestingly, at higher ET-1 concentrations cell proliferation was more pronounced in MCF-7 when compared with MDA-MB-231. Stimulation with ET-1 activated EGFR and downstream signaling proteins (pAKT and pERK) in both cell lines. Incubation of breast cancer cells with ET-1 for 48 hours had different effect on total EGFR level: 3 fold increase of total EGFR was seen in MCF-7, while no change was detected in MDA-MB-231. siRNA against ETAR decreased ET-1 induced cell proliferation and reduced total EGFR level in MCF-7. Conclusions: These observations suggest that ET-1/ETAR plays an important role in survival and proliferation of breast cancer cells. However, those effects are diverse in different subtypes of breast cancer. Our results may represent an improved selective targeted treatment strategy, especially for estrogen receptor positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-06.