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J. Biol. Chem., Vol. 279, Issue 41, 43261-43272, October 8, 2004

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Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice^*

Amy E. Moran, Daniel H. Hunt, Sara H. Javid, Mark Redston¶, Adelaide M. Carothers||**, and Monica M. Bertagnolli

From the Department of Surgery, Weill College of Medicine of Cornell University, and ^||Strang Cancer Prevention Center, New York, New York 10021 and the Departments of Surgery and ^¶Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115

Overexpression of the epidermal growth factor receptor (EGFR) and its increased tyrosine kinase activity are implicated in colorectal cancer (CRC) development and malignant progression. The C57BL/6J-Min/+ (Min/+) mouse is a model for CRC and develops numerous intestinal adenomas. We analyzed the normal mucosa of Min/+ and Apc^+/+ (WT) littermate mice together with Apc-null adenomas to gain insight into the roles of Egfr in these intestinal tissues. Protein analyses showed that Egfr activity was highest in the tumors, and also up-regulated in Min/+ relative to WT enterocytes. Expression of ubiquitylated Egfr (Egfr-Ub) was increased in Min/+ enterocytes and tumors. Tumors exhibited increased association of Egfr with clathrin heavy chain (CHC), Gab1, and p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and tumors also overexpressed c-Src, PDK1, and Akt. Immunohistochemistry for Akt-p-Ser473 revealed a low level of this active kinase in Min/+ and WT enterocytes and its strong presence in tumors. Prostaglandin E₂ (PGE₂) is a product of cyclooxygenase-2 (Cox-2) activity that is up-regulated in Min/+ tumors and transactivates Egfr. PGE₂ expression was significantly higher in untreated Min/+ tumors and reduced by treatment with the Cox-2 inhibitor, celecoxib. Dietary administration of this NSAID also inhibited Egfr activity in tumors. Increased activation of the EGFR-PI3K-Akt signaling pathway in tumors relative to Apc^+/+ and Apc^Min/+ enterocytes provides potential opportunities for therapeutic interventions to differentially suppress tumor formation, promotion, progression, and/or recurrence.

Received for publication, April 16, 2004 , and in revised form, July 26, 2004.

^* This work was supported by NCI Grant R29CA74162 from the National Institutes of Health (to M. M. B.), the Irving Weinstein Foundation (to A. M. C.), and the National Institutes of Health Surgical Oncology Research Training Grants T32-CA68971 (to D. H. H.) and T32-CA09535 (to S. H. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Brigham and Women's Hospital, Dept. of Surgery, 75 Francis St., Carrie Hall, Rm. 116, Boston, MA 02115.

To whom correspondence should be addressed: Dept. of Surgery, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-8910; Fax: 617-582-6177; E-mail: mbertagnolli{at}partners.org.

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