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

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    Authors
    Kok, M
    Zwart, W
    Holm, C
    Fles, R
    Hauptmann, M
    Van't Veer, L
    Wessels, L
    Neefjes, J
    Stål, O
    Linn, S
    Landberg, Göran
    Michalides, R
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    Affiliation
    Department of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    Issue Date
    2011-01
    
    Metadata
    Show full item record
    Abstract
    Phosphorylation of estrogen receptor α at serine 305 (ERαS305-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 ERαS305-P (PKA/ERαS305-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 ERαS305-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/ERαS305-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/ERαS305-P (P = 0.037). Elevated PAK1 and PKA/ERαS305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ERαS305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.
    Citation
    PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer. 2011, 125 (1):1-12 Breast Cancer Res Treat
    Journal
    Breast Cancer Research and Treatment
    URI
    http://hdl.handle.net/10541/120246
    DOI
    10.1007/s10549-010-0798-y
    PubMed ID
    20213082
    Type
    Article
    Language
    en
    ISSN
    1573-7217
    ae974a485f413a2113503eed53cd6c53
    10.1007/s10549-010-0798-y
    Scopus Count
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    All Paterson Institute for Cancer Research

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