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Background:Amplification,over-expression,and/or hyperactivity of ErbB-2 occur in 30-50% of breast tumors which include both luminal B and the HER2+ subtypes.Metastatic breast tumors that overexpress ErbB-2 are difficult to treat and generally resistant to trastuzumab or lapatinib.We have recently published that overexpression of ErbB-2 suppresses Notch-1 activity and this is reversed by inhibitors ofErbB-2,trastuzumab or a tyrosine kinase inhibitor (Osipo et al.,2008.Oncogene).Furthermore,we demonstrated that trastuzumab resistance is reversed when Notch-1 is downregulated by siRNA or when cells are treated with a gamma-secretase inhibitor.Overexpression of IGF-1R and/or downregulation of PTEN,and p27Kip 1 have been shown to be very sensitive markers of trastuzumab resistance.Based on our results and what is known from the literature,we asked by what mechanism Notch-1 contributes to trastuzumab resistance and can a combination therapy prevent or reverse the resistant phenotype by using a pre-clinical in vivo model.