The estrogen receptor alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships

Antonio Russo, Reiss, Lanzino, Sisci, Cecilia Garofalo, Morelli, Andò, Garcia, Eva Surmacz, Sandra Cascio

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Abstract

Background: Insulin receptor substrate 1 (IRS-1) is a signaling molecule that exerts a key role in mediating cross talkbetween estrogen receptor a (ERa) and insulin-like growth factor 1 (IGF-1) in breast cancer cells. Previously, wedemonstrated that a fraction of IRS-1 binds ERa, translocates to the nucleus, and modulates ERa-dependenttranscription at estrogen response elements (ERE). Here, we studied structure–function relationships of the ERa:IRS-1complex under IGF-1 and/or estradiol (E2) stimulation.Materials and methods: ERa and IRS-1 deletion mutants were used to analyze structural and functional ERa/IRS-1interactions. IRS-1 binding to ERE and IRS-1 role in ERa-dependent ERE transcription was examined by chromatinimmunoprecipitation and gene reporter analysis, respectively. The requirement for IRS-1 in ERa function was testedwith RNAi technology.Results: Nuclear translocation of IRS-1 was induced by E2, IGF-1, and a combination of both stimuli. ERa/IRS-1binding was direct and involved the activation function-1 (AF-1)/DNA binding domain (DBD) region of ERa and twodiscrete regions of IRS-1 (the N-terminal pleckstrin homology domain and a region within the C-terminus). IRS-1 knockdown abrogated IGF-1-dependent transcriptional activity of unliganded ERa, but induced the activity of liganded ERa.Conclusions: ERa/IRS-1 interactions are direct and involve the ERa AF-1/DBD domain and IRS-1 domains mappingwithin N- and C-terminus. IRS-1 may act as a repressor of liganded ERa and coactivator of unliganded ERa.
Lingua originaleEnglish
pagine (da-a)81-85
Numero di pagine5
RivistaAnnals of Oncology
Volume18
Stato di pubblicazionePublished - 2007

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All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

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Russo, A., Reiss, Lanzino, Sisci, Garofalo, C., Morelli, Andò, Garcia, Surmacz, E., & Cascio, S. (2007). The estrogen receptor alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships. Annals of Oncology, 18, 81-85.