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  • The EMBO Journal (2007) 26, 3534 - 3544
  • doi:10.1038/sj.emboj.7601791

Published online: 12 July 2007

PKA-induced resistance to tamoxifen is associated with an altered orientation of ERalpha towards co-activator SRC-1

Wilbert Zwart1, Alexander Griekspoor1, Valeria Berno2, Kim Lakeman1, Kees Jalink3, Michael Mancini2, Jacques Neefjes1 and Rob Michalides1

  1. Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA
  3. Department of Cellular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence to:

Rob Michalides, Department of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, NH 1066 CX, The Netherlands. Tel.: +31205122022; Fax: +31205122029; E-mail: r.michalides@nki.nl

Received 24 May 2007; Accepted 15 June 2007

Resistance to tamoxifen is observed in half of the recurrences in breast cancer, where the anti-estrogen tamoxifen acquires agonistic properties for transactivating estrogen receptor alpha (ERalpha). In a previous study, we showed that protein kinase A (PKA)-mediated phosphorylation of serine 305 (S305) of ERalpha results in resistance to tamoxifen. Now, we demonstrate that phosphorylation of S305 in ERalpha by PKA leads to an altered orientation between ERalpha and its coactivator SRC-1, which renders the transcription complex active in the presence of tamoxifen. This altered orientation involves the C-termini of ERalpha and SRC-1, which required a prolonged AF-1-mediated interaction. This intermolecular reorientation as a result of PKA-mediated phosphorylation of ERalpha-S305 and tamoxifen binding provides a unique model for resistance to the anticancer drug tamoxifen.

  • Keywords:

    • estrogen receptor alpha,
    • FRET,
    • protein kinase A,
    • SRC-1,
    • tamoxifen resistance