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Antitumor Activity of Epidermal Growth Factor Receptor–Related Protein Is Mediated by Inactivation of ErbB Receptors and Nuclear Factor-B in Pancreatic Cancer

¹ Department of Pathology; ² Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine; ³ Department of Internal Medicine, Veterans Affairs Medical Center, Detroit, Michigan; ⁴ Department of Biochemistry and Molecular Biology, Capital University of Medical Sciences, Beijing, China; and ⁵ Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Fazlul H. Sarkar, 740 HWCRC, 110 East Warren Avenue, Detroit, MI 48201. Phone: 313-576-8327; Fax: 313-576-8389; E–mail: fsarkar{at}med.wayne.edu.

The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-B activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins. (Cancer Res 2006; 66(2): 1025-32)

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