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Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer

¹ Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Græcia; ² Unità Operativa di Chirurgia Generale Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy; ³ Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Milan, Italy; ⁴ Department of Biochemistry and Molecular Biology and the USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; and ⁵ Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università di Napoli Federico II, e NOGEC-CEINGE, Biotecnologie Avanzate, Napoli, Italy

Requests for reprints: Antonio Brunetti, Cattedra di Endocrinologia, Policlinico Mater Domini, Università di Catanzaro Magna Græcia, Via T. Campanella 115, Catanzaro, Italy. Phone: 39-961-712257; Fax: 39-961-775373; E-mail: brunetti{at}unicz.it.

Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis. (Cancer Res 2006; 66(10): 5085-93)

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