Abstract 4864: Targeting MET and ERBB2 signaling in aggressive breast cancers
Authors: Graveel Carrie R. , Paulson Amanda , Linklater Erik , Berghuis Bree , Feenstra Kristin , Melnik Marianne , Woude George Vande 
Published: August 2012

Abstract
In spite of clinical advancements, tumors that no longer depend on ER/PR and ERBB2 signaling are clinically aggressive and have the poorest prognosis. Few effective treatment options exist for basal or trastuzumab-resistant ERBB2 breast cancers. Understanding the signaling pathways that drive these aggressive breast cancer subtypes is critical to the development of successful therapeutics. The receptor tyrosine kinase MET is overexpressed in 20-30% of breast cancers and correlates with poor patient outcome, independent of ERBB2 expression. Previously, we determined that MET is expressed in the majority of breast cancers. Most importantly, we determined that high MET expression correlated with ERneg/ERBB2neg tumors and the basal subtype. These studies indicate that MET may serve as a novel therapeutic target for those patients with the most aggressive tumors and currently, the fewest therapeutic options. We are utilizing breast cancer cell lines and xenograft mouse models to examine how MET and ERBB2 uniquely influence breast cancer progression. To investigate the effects of MET and/or ERBB2 inhibition we are utilizing lentiviral shRNA knockdown in both basal and luminal cells. We observed that both MET and ERBB2 depletion decrease cell proliferation and invasion. In addition, we have profiled the effects of MET and ERBB2 knockdown on the phosphorylation of 42 receptor tyrosine kinases (RTK) and 44 tyrosine kinases. We observed that downstream signaling at the tyrosine kinase level is minimally affected by downregulation of MET or ERBB2; however, there is significant signaling compensation that occurs at the RTK level through the ERBB family members, EGFR and ERBB3. Currently, we are examining the interaction between MET and the ERBB family in both basal and luminal breast cancer cell lines. In addition, we are measuring the effect of MET or ERBB2 depletion on growth of breast cancer cells in 3D culture. In addition, we have evaluated MET and ERBB2 expression in human invasive breast carcinomas using coimmunostaining and quantitative analysis with the CRi Nuance multispectral imager. We observe that a significant percentage of tumors coexpress MET and ERBB2. Many tumors have significant heterogeneity of MET and ERBB2 expression and have patterns of cells that are METhigh/ERBB2low, METlow/ERBB2high, and METhigh/ERBB2high. We hypothesize that breast cancer cells expressing both MET and ERBB2 (METhigh/ERBB2high) are highly tumorigenic and have an increased proliferative capacity, metastatic potential and chemoresistance. Currently, fresh primary human breast cancer tissue is being transplanted into mammary glands of NOD-SCIDIL2αR mice to determine the impact of MET and ERBB2 expression on tumor growth and metastasis in vivo. These studies will reveal whether MET and ERBB2 have synergistic or exclusive roles in breast cancer progression and how these oncogenes can be targeted for successful therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4864. doi:1538-7445.AM2012-4864