The decision to treat breast cancer patients with Trastuzumab is based on HER2 receptor over-expression or gene amplification.However, even in this selective group of patients, the response rate remains poor and unpredictable.Furthermore, all responders eventually become resistant if Trastuzumab is given as monotherapy.It is still poorly understood how Trastuzumab exerts its mechanism of action and how the acquired resistance to this drug occurs.We have determined a molecular mechanism for acquired resistance to Trastuzumab.We have shown that Trastuzumab does not decrease HER2 phosphorylation despite the effect on HER2 receptor downregulation.HER2 phosphorylation is maintained by activation of EGFR, HER3 and HER4 via their dimerisation with HER2 in HER2 positive breast cancer cells.The activation of EGFR, HER3 and HER4 is due to an upregulation of HER ligands including heregulin and betacellulin.The upregulation of HER ligands is mediated by ADAM 17 through a PKB negative feedback loop.