Abstract 3256: Investigating the intrinsic signaling differences in MET- and ERBB2-driven breast cancers

Abstract

Abstract Understanding the signaling pathways that drive aggressive breast cancers is critical to the development of effective therapeutics. Over 20% of breast cancers overexpress ERBB2 and are associated with an aggressive tumor phenotype and poor outcome. Patients with ERBB2-positive tumors are often treated with the humanized monoclonal antibody trastuzumab, yet the majority of patients develop resistance. Recent studies show that the receptor tyrosine kinase MET is expressed in ERBB2 positive tumors and contributes to trastuzumab resistance in ERBB2-expressing cell lines. Other studies have shown that MET correlates with poor clinical outcome independent of ERBB2. We are utilizing mouse models to examine the intrinsic signaling differences between MET and ERBB2-mediated breast cancers. We have developed a novel mouse model of mutationally activated MET (Metmut) that develops a high incidence of diverse mammary tumors with basal characteristics. Using this mouse model and human breast cancer tissue, we have examined the role of MET in aggressive breast cancers. By gene expression and tissue microarray analysis, we observe that high MET expression in human breast cancers significantly correlates with estrogen receptor negative/ERBB2 negative tumors and with basal breast cancers (Graveel et al., 2009). We performed gene expression analysis on mammary tumors from Metmut mice and activated ErbB2 (Neu-Ndl2-5) mice. Unsupervised hierarchical analysis revealed that solid Metmut tumors clustered separately from Metmut tumors with a mixed pathology and that solid Metmut tumors have expression patterns very similar to ERBB2 tumors. The similarity of solid Metmut tumors to ErbB2 tumors suggests that MET signaling may be influential in ERBB2-driven tumors. To investigate this hypothesis further, we performed a parametric gene set enrichment analysis (PGSEA) and observed that the Ras activation signature was significantly associated with the Metmut mixed tumors. Currently, we are also investigating expression patterns of MET and ERBB2 in human breast cancers by coimmunostaining. Collectively, our studies indicate that MET may play a critical role in the development of the most aggressive breast cancers and may be a rational therapeutic target for trastuzumab-resistant ERBB2 breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3256.