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Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters

Abstract

Insulin receptor substrate 1 (IRS-1) is a major signaling molecule activated by the insulin and insulin-like growth factor I receptors. Recent data obtained in different cell models suggested that in addition to its conventional role as a cytoplasmic signal transducer, IRS-1 has a function in the nuclear compartment. However, the role of nuclear IRS-1 in breast cancer has never been addressed. Here we report that in estrogen receptor α (ERα)-positive MCF-7 cells, (1) a fraction of IRS-1 was translocated to the nucleus upon 17-β-estradiol (E2) treatment; (2) E2-dependent nuclear translocation of IRS-1 was blocked with the antiestrogen ICI 182,780; (3) nuclear IRS-1 colocalized and co-precipitated with ERα; (4) the IRS-1:ERα complex was recruited to the E2-sensitive pS2 gene promoter. Notably, IRS-1 interaction with the pS2 promoter did not occur in ERα-negative MDA-MB-231 cells, but was observed in MDA-MB-231 cells retransfected with ERα. Transcription reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 inhibits ERα activity at estrogen-responsive element-containing DNA. In summary, our data suggested that nuclear IRS-1 interacts with ERα and that this interaction might influence ERα transcriptional activity.

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Acknowledgements

This research was supported in part by the following grants and awards: DOD Breast Cancer Research Program DAMD17-99-1-9407 (ES), DAMD17-01-1-0651 (ES), DAMD17-01-1-0320 (SdR), NIH CA87391 (ERS); Cancer Research Foundation of America F55401 (CG and ES).

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Correspondence to Eva Surmacz.

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Morelli, C., Garofalo, C., Sisci, D. et al. Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters. Oncogene 23, 7517–7526 (2004). https://doi.org/10.1038/sj.onc.1208014

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