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Human epidermal growth factor receptor 2 (Her2/neu) have been found in ∼25–30% breast tumors and its overexpression is associated with a high risk of relapse, unfavourable prognosis and short survival. Trastuzumab has shown good clinical response in breast tumors overexpressing Her2/neu. Platelet-derived growth factor receptors (PDGFR) α and β are linked with advanced human breast cancers and PDGFRs produced in carcinomas are generally thought to act on the nonepithelial tumor stroma by promoting angiogenesis. Still it is unclear how expression of PDGFRs contributes to the resistance to trastuzumab. We therefore have assessed interactions between epithelial breast cancer cells and human fibroblasts upon trastuzumab treatment in a co-culture model.Both human breast cancer-derived SKRB3 cells and human fibroblast-derived BJH-Tert cells were either mono-cell culture or co-culture in the current study. Upon co-cultured cells were treatment with trastuzumab and PDGF ligand bb, cell growth suppression assays, western blotting as well as PCGF-aa and PCGF-bb stimulations have been applied. In addition, tissue microarray was constructed and Immunohistochemistry was carried out.We found that Her2 overexpessing SKRB3 cells but not BJH-Tert cells derived from human fibroblasts respond to trastuzumab. This indicates that the effect of trastuzumab on these cells is Her2 dependent and this is in agreement with previously published data. Major finding of the present study is that the presence of PDGFRs can minimize the efficacy of trastuzumab in SKRB3 co-cultured with BJH-Tert cells. Furthermore, we found that AKT oncoprotein is a direct target of PDGF receptors to play role in mitigating sensitivity of trastuzumab in Her2-signaling pathway. Immunohiochemistry staining demonstrates that PDGF receptor beta is a crucial factor that can monitor disease relapse and patient survival.We demonstrated that PDGFRs impair sensitivity to trastuzumab in a co-cultured breast cancer cell model through PIK3-AKT pathway. Expression of PDGF receptor beta in the tumor tightly related with disease relapse and patient survival. Our findings suggest that a more aggressive therapeutical protocol need to be setting up to improve the treatment of the subgroup of breast cancer patients with Her2-positive tumors which overexpress PDGFRs.