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PKA-induced phosphorylation of ER alpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer

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Author

  • Marleen Kok
  • Wilbert Zwart
  • Caroline Wigerup
  • Renske Fles
  • Michael Hauptmann
  • Laura J. Van't Veer
  • Lodewyk F. A. Wessels
  • Jacques Neefjes
  • Olle Stal
  • Sabine C. Linn
  • Göran Landberg
  • Rob Michalides
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Summary, in English

Phosphorylation of estrogen receptor alpha at serine 305 (ER alpha S305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ER alpha S305-P (PKA/ER alpha S305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ER alpha S305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ER alpha S305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ER alpha S305-P (P = 0.037). Elevated PAK1 and PKA/ER alpha S305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ER alpha S305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

Department/s

  • Pathology, Malmö
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2011

Language

English

Pages

1-12

Publication/Series

Breast Cancer Research and Treatment

Volume

125

Issue

1

Document type

Journal article

Publisher

Springer

Topic

  • Cancer and Oncology

Keywords

  • Tamoxifen sensitivity
  • Phosphorylation of ER
  • PKA
  • PAK1
  • Breast cancer

Status

Published

Research group

  • Pathology, Malmö

ISBN/ISSN/Other

  • ISSN: 1573-7217