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Coxsackie and Adenovirus Receptor Promotes Adenocarcinoma Cell Survival and Is Expressionally Activated after Transition from Preneoplastic Precursor Lesions to Invasive Adenocarcinomas

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany, and ² Department of Obstetrics and Gynecology, Albert-Ludwigs-University, Freiburg, Germany

Requests for reprints: Ingo B. Runnebaum, I. Frauenklinik der Ludwig-Maximilians-Universitaet, Maistrasse 11, D-80337 Munich, Germany. Phone: 49-89-5160-4510; Fax: 49-89-5160-4748; E-mail: ingo.runnebaum{at}med.uni-muenchen.de.

Purpose: The cell adhesion protein, coxsackie and adenovirus receptor (CAR), is differentially expressed in various human adenocarcinomas. We analyzed the role of differential CAR expression during tumorigenesis and in cell survival of adenocarcinomas.

Experimental Design: In a murine mammary cancer model, a syngenic preneoplastic mammary tissue was implanted into the mammary fat pads of syngenic female BALB/c mice. CAR expression was determined by semiquantitative reverse transcription-PCR in the preneoplastic noninvasive precursor lesions and the developing invasive adenocarcinomas. Cell clones overexpressing CAR were generated and tested for their response to apoptotic factors and for the expression of apoptosis relevant proteins by reverse transcription-PCR and Western blot analysis.

Results: In comparison of preneoplastic precursor lesions with established adenocarcinomas, CAR expression was enhanced 2- to 5-fold in all six tissues which had survived and transformed into invasive adenocarcinomas. When stable CAR-overexpressing cell clones of the human cancer cell lines HeLa, CaSki, and A2780 were compared with the parental cell lines, 1.5- to 6-fold more cells survived application of tumor necrosis factor–related apoptosis-inducing ligand or growth factor withdrawal. CAR-enhanced cell survival was accompanied by reduced activation of caspase 3 and enhanced expression of bcl-2 or bcl-XL, depending on the cell type tested. Up-regulation of bcl-2 was found in all CAR-expressing adenocarcinomas of the murine cancer model.

Conclusions: CAR expression is enhanced after transition from preneoplastic precursor lesions to neoplastic mammary cancer outgrowths. Enhanced CAR expression can promote cancer cell survival. These data suggest differential expression of CAR as a new factor in tumorigenesis.

Key Words: Coxsackie adenovirus receptor • apoptosis • TRAIL • bcl-2 • bcl-XL