Abstract 3120: Aberrant activation of ERBB3 oncogenic signaling in human hepatocellular carcinoma

Abstract

Abstract Background & aims: Recent evidence that ERBB3 is responsible for tumor resistance to EGFR or ERBB2 targeted therapies highlighted its crucial role in the oncogenic signaling of EGFR family. However, its roles in hepatocelluar carcinoma (HCC) remain unclear. Methods: Expression and phosphorylation of ERBB3 was examined in HCC tissues and cells. Gene number was determined using fluorescence in situ hybridization. Roles of EGEF, ERBB2, and neuregulin in phosphorylation of ERBB3 were evaluated via small-interference RNAs to silence their expression. The effects of ERBB3 on cell proliferation, invasion and tumorigenesis were assayed in vitro and in vivo. Results: Overexpression of ERBB3 was associated with a higher recurrence (P=0.000), and a worse prognosis (P=0.004). Gain of ERBB3 gene number was found in most HCC cells. EGFR, ERBB2, neuregulin and phosphorylated ERBB3 were detected in HCC cells. Phosphorylation of ERBB3 was induced by treatment with the conditioned media of HCC cells, while it was abolished by pre-treatment of the conditioned media with the anti-neuregulin antibodies or by silencing neuregulin expression. Phosphorylation of ERBB3 was suppressed by silencing the expression of ERBB2 but not EGFR. Induction of ERBB3 phosphorylation promoted cell proliferation, invasion and colony formation, while silencing ERBB3 expression suppressed xenograft tumor formation and growth in nude mice. Conclusions: Overexpression of ERBB3, primarily attributable to gene amplification, was associated with a poor prognosis of HCC. Aberrant activation of ERBB3, via an autocrine mechanism by dimerization with ERBB2, enhanced tumorigenesis in vitro and in vivo. The oncogenic signaling of ERBB3 can be the target for anti-HCC therapy. 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 3120.