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Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
¹ Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA
² Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA

(Requests for offprints should be addressed to H Werner; Email: hwerner{at}post.tau.ac.il)

The IGF-I receptor (IGF-IR) has an important role in breast cancer development and progression. Previous studies have suggested that the IGF-IR gene is negatively regulated by a number of transcription factors with tumor suppressor activity, including the Wilms’ tumor protein WT1. The present study was aimed at evaluating the hypothesis that IGF-IR gene transcription in breast cancer cells is under inhibitory control by WT1 and, furthermore, that the mechanism of action of WT1 involves functional and physical interactions with estrogen receptor- (ER). Results of transient coexpression experiments showed that all four predominant isoforms of WT1 (including or lacking alternatively spliced exons 5 and 9) repressed IGF-IR promoter activity by 39–49%. To examine the potential interplay between WT1 and ER in control of IGF-IR gene transcription we employed ER-depleted C4 cells that were generated by clonal selection of ER-positive MCF-7 cells that were maintained in estrogen-free conditions. IGF-IR levels in C4 cells were ~43% of the values in MCF-7 cells whereas WT1 levels in C4 cells were 4.25-fold higher than in MCF-7. Triple cotransfection experiments using an ER expression vector in the absence or presence of WT1 expression vectors, along with an IGF-IR promoter reporter plasmid, revealed that ER stimulated IGF-IR promoter activity whereas coexpression of WT1 abrogated the effect of ER. In addition, co-immunoprecipitation experiments demonstrated a specific association between WT1 and ER. Combined, our results suggest that WT1 suppresses IGF-IR gene transcription in breast cancer cells via a mechanism that involves protein–protein association with ER. As a result of this interaction, the ability of ER to transactivate the IGF-IR promoter is abrogated. These findings are consistent with a potential tumor suppressor role for WT1 in breast cancer and suggest that WT1 inactivation in tumoral cells may result in deregulated IGF-IR gene expression and enhanced mitogenic activation by locally produced and/or circulating IGFs.

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