Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and 
inhibit the function of the human epidermal growth factor receptor 2 
(HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several 
types of HER2-overexpressing epithelial tumors, such as breast and metastatic 
gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, 
however, still occur in a subset of patients treated with regimens including 
trastuzumab, despite significant improvements in response rates, survival and 
quality of life. To investigate the potential mechanisms of acquired therapeutic 
resistance to trastuzumab, we developed a preclinical model of human ovarian 
cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding 
changes in gene expression profiles. SKOV-3 HR cells were developed by in vivo 
serial passaging of parental trastuzumab-sensitive SKOV-3 cells. Following four 
rounds of serial transplantation of 'break-through' xenograft tumors under 
trastuzumab treatment, significant and reproducible differences in the effects 
of trastuzumab treatment between SKOV-3 HR and SKOV-3 cells in vivo and in vitro 
were revealed. SKOV-3 HR cells retained HER2 protein expression but were 
unaffected by the antiproliferative effects of trastuzumab. The trastuzumab 
binding affinity for SKOV-3 HR cells was diminished, despite these cells having 
more binding sites for trastuzumab. Microarray expression profiling (MEP) was 
performed to determine the genes involved in the resistance mechanism. 
Functional analysis revealed the differential expression of genes potentially 
involved in angiogenesis, metastasis, differentiation and proliferation, such as 
mucin1 (MUC1). Immunohistochemical staining of SKOV-3 HR cells demonstrated a 
marked overexpression of MUC1. Based on these data, we hypothesize that the 
overexpression of MUC1 may hinder trastuzumab binding to HER2 receptors, 
abrogating the antitumor effects of trastuzumab and thus could contribute to 
resistance to therapy. Moreover, the resultant MEP preclinical gene signature in 
this preclinical model system may provide the basis for further investigation of 
potential clinical mechanisms of resistance to trastuzumab.