O1-11-5 - Treatment of Breast Cancer with Trastuzumab Can Be Directed and Optimized by Level of Pdgf-Beta Receptor in Tumors

Abstract

Trastuzumab has shown good clinical response in breast tumors overexpressing Her2/neu. Platelet-derived growth factor receptors (PDGFR) alpha and beta 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 treatment of human breast cancer. We therefore have assessed interactions between epithelial breast cancer cells and human fibroblasts upon trastuzumab treatment in a co-culture model. By using different molecular biological assay, we found that Her2 overexpessing SKRB3 cells but not BJH-Tert cells derived from human fibroblasts respond to trastuzumab. This indicating that effect of trastuzumab in these cells is Her2-dependent and this is in agreement with previously published data. Major finding of present study is that presence of PDGFRs can minimize 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.In order to further validating our findings, a TMA-based Immunohiochemistry study is carried out on more than 300 cases from a randomized study of adjuvant trastuzumad treatment. Strong indications have been obtained between disease relapse, patient survival upon treatment of trastuzumad and stromal PDGF-receptor status. Our studies therefore demonstrated that PDGFRs impair sensitivity to trastuzumab in co-experimental model as well as in human breast yumors are tightly related with expression level of PDGF beta-receptor. Our findings suggest needs to more aggressive therapeutical efforts for the subgroup of breast cancer patients with Her2-positive tumors which overexpress PDGFRs.