Abstract 3444: EGFR-dependent matriptase activation in ErbB2-amplified breast cancer

Abstract

Abstract Of the nearly 250,000 new breast cancer cases expected annually, nearly 25% will have ErbB2 (HER2) gene amplification, which is associated with increased growth signaling, more aggressive disease, and poor patient prognosis. Matriptase is a type II transmembrane serine protease that plays a role in normal epithelial cell biology. The expression and activation of matriptase are tightly regulated in normal cells partly through co-expression with endogenous inhibitor, HAI-1, which rapidly inhibits the protease, once activated, by the formation of a high affinity complex. Matriptase has oncogenic potential when its regulation is deranged and it activates downstream substrates known to play a role in tumor progression such as pro-HGF. ErbB2 activity can regulate matriptase activity in prostate cancer and so we set out to elucidate the relationship between ErbB2 and matriptase in ErbB2-amplified breast cancer. SKBR3, AU565, and ErbB2 transfected MCF7 cells (MB7) were used to explore the relationship between ErbB2 levels and matriptase activation as they express higher levels of ErbB2 compared with MCF7 cells. Under standard growth conditions, high level of ErbB2 activation was associated with extensive matriptase activation. Activation of ErbB2 by stimulating EGFR with EGF resulted in increased matriptase activation. Inhibition of ErbB2 activity by serum deprivation or Lapatinib (a dual ErbB2 and EGFR kinase inhibitor) treatment resulted in decreased matriptase activation. Treatment with Lapatinib or the EGFR-specific inhibitor, Gefitinib, blocked matriptase activation whereas the ErbB2 inhibitor, AG825, has no effect. Using inhibitors of downstream signaling pathways, EGFR-induced matriptase activation was shown to be mediated by PI3K signaling. Further elucidation of the pathway is ongoing. In summary, our data suggest that EGFR signaling in this context modulates matriptase activation, which may also contribute to breast cancer progression. Citation Format: Darius Gaymon. EGFR-dependent matriptase activation in ErbB2-amplified breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3444.