Abstract 3022: MET and ERBB2 are coexpressed in ERBB2+ breast cancers and contribute to innate resistance.

Abstract Breast cancers display a remarkable phenotypic diversity that is exploited to promote both tumor progression and therapeutic resistance. Recent studies in several types of cancer have highlighted the significance of intratumoral heterogeneity on both innate and acquired resistance to tyrosine kinase inhibitors. Tumor plasticity is supported by the heterogeneous expression of receptor tyrosine kinases (RTKs) and the robustness that the overlapping signaling networks provide. Therefore a thorough understanding of the intratumoral heterogeneity is necessary for the development of effective therapeutic strategies. The receptor tyrosine kinase MET is overexpressed in 20-30% of breast cancers and correlates with poor patient outcome. Previously, we determined that high MET expression correlated with ERneg/ERBB2neg and basal-like breast cancers. These results and the efficacy of MET inhibitors in other cancers suggest that MET may be an effective clinical target for aggressive breast cancer subtypes. Recent studies have exposed interactions between MET and the ERBB receptor family in the progression and therapeutic resistance of several cancers. Since MET, ERBB2, and EGFR are known to be highly expressed in aggressive breast cancer subtypes, it is critical that we understand the relationships between these receptors in order to develop effective treatment strategies. In this study, we interrogated the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancers and a breast cancer cell line. Using coimmunostaining and quantitative multispectral analysis, we observed that a significant percentage of ERBB2+ tumors coexpress MET and ERBB2. These tumors display significant heterogeneity and have subpopulations of cells that are METhigh/ERBB2low, METlow/ERBB2high, and METhigh/ERBB2high. In a METhigh/ERBB2high breast cancer cell line, we observed that MET depletion results in increased ERBB2 activation and conversely ERBB2 depletion results in increase MET activation. Neither EGFR or ERBB3 compensated for MET or ERBB2 knockdown. The loss of both MET and ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. MET and ERBB2 knockdown did decrease proliferation but neither alone was able to abolish all cell growth. These results in addition to the heterogeneous expression of MET and ERBB2 in breast cancers have significant clinical implications on potential therapeutic strategies for breast cancer patients. Citation Format: Amanda Paulson, Erik Linklater, Bree Berghuis, Marianne Melnik, George Vande Woude, Carrie R. Graveel. MET and ERBB2 are coexpressed in ERBB2+ breast cancers and contribute to innate resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3022. doi:10.1158/1538-7445.AM2013-3022