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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

Kok, Marleen; Zwart, Wilbert; Wigerup, Caroline LU ; Fles, Renske; Hauptmann, Michael; Van't Veer, Laura J.; Wessels, Lodewyk F. A.; Neefjes, Jacques; Stal, Olle and Linn, Sabine C., et al. (2011) In Breast Cancer Research and Treatment 125(1). p.1-12
Abstract
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... (More)
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. (Less)
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published
subject
keywords
Tamoxifen sensitivity, Phosphorylation of ER, PKA, PAK1, Breast cancer
in
Breast Cancer Research and Treatment
volume
125
issue
1
pages
1 - 12
publisher
Springer
external identifiers
  • wos:000284956400001
  • scopus:78651089973
ISSN
1573-7217
DOI
10.1007/s10549-010-0798-y
language
English
LU publication?
yes
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50be076f-13c6-46b2-bef1-aebd30836411 (old id 1774207)
date added to LUP
2011-02-01 09:57:37
date last changed
2017-09-10 04:16:20
@article{50be076f-13c6-46b2-bef1-aebd30836411,
  abstract     = {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.},
  author       = {Kok, Marleen and Zwart, Wilbert and Wigerup, Caroline and Fles, Renske and Hauptmann, Michael and Van't Veer, Laura J. and Wessels, Lodewyk F. A. and Neefjes, Jacques and Stal, Olle and Linn, Sabine C. and Landberg, Göran and Michalides, Rob},
  issn         = {1573-7217},
  keyword      = {Tamoxifen sensitivity,Phosphorylation of ER,PKA,PAK1,Breast cancer},
  language     = {eng},
  number       = {1},
  pages        = {1--12},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {PKA-induced phosphorylation of ER alpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer},
  url          = {http://dx.doi.org/10.1007/s10549-010-0798-y},
  volume       = {125},
  year         = {2011},
}