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¹ Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland; ² Department of Biology, Clarkson University, Potsdam, New York; and ³ Departments of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany

Requests for reprints: Craig D. Woodworth, Department of Biology, Clarkson University, Potsdam, NY 13699. Phone: 315-268-2391; Fax: 315-268-7118. E-mail: woodworth{at}clarkson.edu

The epidermal growth factor receptor (EGFR) is overexpressed in several types of human cancer, and inhibition of EGFR function is a promising strategy for cancer therapy. We used cDNA microarrays to examine alterations in gene expression after treatment of carcinoma cells with PD153035, a specific and reversible inhibitor of EGFR function. When human cervical carcinoma cells were grown on a collagen substrate in three-dimensional organotypic culture, untreated cells expressed high levels of EGFR RNA and invaded the underlying collagen. Blocking EGFR function decreased DNA synthesis and inhibited invasion in a dose-dependent manner. Microarray analyses identified 312 genes that were significantly increased or decreased in expression after EGFR inhibition. Many could be classified into one of four functional groups including genes that (a) stimulate inflammation and innate immunity, (b) promote cell attachment, (c) enhance apoptosis, and (d) inhibit cell cycle progression. PD153035 induced a dose-dependent activation of nuclear factor B, a transcription factor that stimulates proinflammatory gene expression. Our results identify alterations in gene expression caused by EGFR inhibition and show that this response varies significantly in different cell lines.

Key Words: epidermal growth factor receptor • microarray • inflammation • cervical cancer • NF-B

Grant support: National Cancer Institute grant 1R15CA101873-01A1.

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.

Note: E. Michael is currently at the Department of Dermatology, University of Michigan Medical School.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org).

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Received 9/ 8/04; revised 12/ 9/04; accepted 2/ 7/05.