1. ¹Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
2. ²Postgraduate School in Clinical Pathology, University of Calabria, Cosenza, Italy
3. ³McGill University, Lady Davis Institute for Medical Research, Montreal, Canada
4. ⁴Section of Molecular Oncology, Department of Oncology, University of Palermo, Palermo, Italy
5. ⁵Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO 65212, USA

Correspondence: E Surmacz, Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St, BLSB 631, Philadelphia, PA 19107, USA. E-mail: eva.surmacz@jefferson.edu

⁶These two authors contributed equally to this work

Received 20 January 2004; Revised 24 June 2004; Accepted 24 June 2004; Published online 16 August 2004.

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 (ER)-positive MCF-7 cells, (1) a fraction of IRS-1 was translocated to the nucleus upon 17--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 ER; (4) the IRS-1:ER complex was recruited to the E2-sensitive pS2 gene promoter. Notably, IRS-1 interaction with the pS2 promoter did not occur in ER-negative MDA-MB-231 cells, but was observed in MDA-MB-231 cells retransfected with ER. Transcription reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 inhibits ER activity at estrogen-responsive element-containing DNA. In summary, our data suggested that nuclear IRS-1 interacts with ER and that this interaction might influence ER transcriptional activity.