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Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in human breast cancers. It is known to drive tumor growth and progression and represents a prominent target in breast cancer therapy. The endothelin (ET) system, in particular ET-1 and its receptor ETAR, is of major relevance for breast cancer growth and invasion. Having previously demonstrated coexpression of ETAR and HER2 in breast tumors, this study was designed to investigate molecular interactions of HER2 (including the epidermal growth factor receptor EGFR as its major coreceptor) and ET signaling, and the potential benefit of a combined anti-HER2/ETAR treatment in human breast cancer cells. Dual HER2-ETAR targeting utilizing trastuzumab (monoclonal anti-HER2 antibody) and the ETAR antagonist atrasentan was superior to each agent alone in inhibiting basal and EGF-induced proliferation and invasion of HER2-overexpressing BT-474 and SK-BR-3 cells. EGF-induced invasion was partially inhibited by atrasentan alone, suggesting the involvement of ETAR in EGF receptor mediated invasion of breast cancer cells. Moreover, secretion of the pro-invasive ET-1 was shown to be induced by EGF via EGFR and HER2, including MAPK-dependent signaling. In turn, an ET-1/ETAR-dependent regulation of EGFR protein expression and phosphorylation (at Tyr845) was observed, which may contribute to the additional anti-proliferative and anti-invasive effects of atrasentan on trastuzumab treated cells; reconfirming, atrasentan failed to enhance inhibitory effects of EGFR-targeted agents. This study suggests complex interactions between HER2/EGFR and ET pathways in breast cancer and supports the hypothesis that dual HER2-ETAR targeting may represent a highly effective approach in breast cancer treatment.