title: Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment.
abstract: 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 kappaB, 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.
authors.affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland, USA. woodworth@clarkson.edu
authors.forename: Craig D
authors.initials: CD
authors.lastname: Woodworth
authors.forename: Evan
authors.initials: E
authors.lastname: Michael
authors.forename: Dan
authors.initials: D
authors.lastname: Marker
authors.forename: Sarah
authors.initials: S
authors.lastname: Allen
authors.forename: Laura
authors.initials: L
authors.lastname: Smith
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation; D016328:NF-kappa B / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D015345:Oligonucleotide Probes / Q000737:chemistry; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D011799:Quinazolines; D014443:Tyrosine; D012313:RNA; D003094:Collagen; D004247:DNA; D066246:ErbB Receptors; D001973:Bromodeoxyuridine; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline