We used an in vivo tumor product that overexpresses p95 HER2 and show it to be resistant to the signaling and anti-tumor effects of Trastuzumab. We find that both full-length and p95 HER2 interact with the HSP90 chaperone protein and are degraded in tumor cells exposed to HSP90 inhibitors in tissue culture and in vivo. Loss of expression of p95 natural product libraries HER2 is accompanied by downregulation of the PI3K/AKT and ERK signaling pathways and inhibition of cell growth. Chronic administration of HSP90 inhibitors in vivo in continual loss of HER2 and p95 HER2 expression and inhibition of AKT service as well as induction of apoptosis and complete inhibition of tumor growth in Trastuzumab immune, p95 HER2 overexpressing models. Hence, p95 HER2 is an HSP90 client protein, the appearance and function that may be effectively suppressed in vivo by HSP90 inhibitors. HSP90 inhibition is therefore a potentially effective therapeutic technique for p95 HER2 mediated Trastuzumab resistant breast cancer. The HER2/ERBB2 Endosymbiotic theory receptor tyrosine kinase is amplified in 20-30 of cases of breast cancer. Audio of HER2 is associated with activation of receptor tyrosine kinase dependent signaling pathways, especially HER2/HER3 dimer dependent activation of PI3K/AKT signaling, with attendant increases in N cyclin appearance, de-regulation of growth and desensitization of the cyst to apoptotic stimuli. HER2 audio or mutational service is oncogenic in several model systems and it is likely that, in these tumors, it is necessary for tumor initiation, progression or preservation of the transformed phenotype. Trastuzumab, a humanized, monoclonal antibody that binds to HER2, has marked medical advantage for patients with early or late-stage breast cancers in which HER2 is overexpressed. Trastuzumab Decitabine Dacogen is thought to exert numerous anti-tumor outcomes including inhibition of HER2 signaling, leading to down-regulation of the PI3K AKT and RAS ERK signaling pathways, and, furthermore, activation of antibody dependent cell mediated cytotoxicity. The antibody has anti-tumor activity when given alone and also improves the potency of specific chemotherapeutic agents, most notably taxanes, probably by inhibiting antiapoptotic signaling pathways. Despite these pleiotropic activities, innate or acquired resistance to Trastuzumab based therapy is just a common clinical phenomenon, particularly in patients with metastatic illness, in whom cyst development is practically invariable. A few likely resistance elements have been described in model systems, while none of these has been completely validated in patients. These generally include hyperactivation of the PI3K AKT pathway due to mutation or reduced expression of PTEN or mutational activation of the p110 subunit of PI3K, upregulation of other receptor tyrosine kinases such as EGFR, h MET, or IGF 1R, and accumulation of truncated forms of HER2.