Notch-1 activates ErbB-2 through a PEA3-dependent mechansim.

Abstract Abstract #6015 Over-expression or gene amplification of ErbB-2 occurs in 25% of breast cancer which is associated with malignancy, poor overall survival, and resistance to some anti-hormonal therapies. Although trastuzumab has had a tremondous impact on survival, resistance results within the first year of treatment in 15% of cases and remains a major problem in the metastatic setting. We have recently published (Osipo et al., 2008. Oncogene) that the expression and activity of Notch-1, a potent breast oncogene and cell fate determinant is increased in ErbB-2 positive breast cancer cells in response to trastuzumab. Furthermore, we have shown that Notch-1 might contribute to trastuzumab resistance. In the current study, we asked whether Notch-1 could activate ErbB-2. Results demonstrated that a Notch inhibitor, γ-secretase inhibitor (GSI) or a Notch-1 siRNA decreased tyrosine phosphorylated and total ErbB-2 expression in SKBR3, MCF-7, and MDA-MB-231 cells. Furthermore, overexpression of constitutively active Notch-1 increased tyrosine phosphorylated ErbB-2 and reversed the inhibition by a GSI. ErbB-2 promoter activity using a luciferase reporter construct was decreased by Notch-1 siRNA only when the PEA3 Ets binding site was mutated. These results suggest that Notch-1 is an activator of ErbB-2 in breast cancer cells that express low or inactive PEA3. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6015.