The WT1 Wilms' tumor suppressor gene product interacts with estrogen receptor-alpha and regulates IGF-I receptor gene transcription in breast cancer cells.
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| Abstract |
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-alpha (ERalpha). 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 ERalpha 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 approximately 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 ERalpha expression vector in the absence or presence of WT1 expression vectors, along with an IGF-IR promoter reporter plasmid, revealed that ERalpha stimulated IGF-IR promoter activity whereas coexpression of WT1 abrogated the effect of ERalpha. In addition, co-immunoprecipitation experiments demonstrated a specific association between WT1 and ERalpha. Combined, our results suggest that WT1 suppresses IGF-IR gene transcription in breast cancer cells via a mechanism that involves protein-protein association with ERalpha. As a result of this interaction, the ability of ERalpha 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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| Authors | Naama Reizner, Sharon Maor, Rive Sarfstein, Shirley Abramovitch, Wade V Welshons, Edward M Curran, Adrian V Lee, Haim Werner |
| Journal | Journal of molecular endocrinology (J Mol Endocrinol) Vol. 35 Issue 1 Pg. 135-44 (Aug 2005) ISSN: 0952-5041 [Print] England |
| PMID | 16087727 (Publication Type: Journal Article) |
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