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dc.contributor.authorKok, Men
dc.contributor.authorZwart, Wen
dc.contributor.authorHolm, Cen
dc.contributor.authorFles, Ren
dc.contributor.authorHauptmann, Men
dc.contributor.authorVan't Veer, Len
dc.contributor.authorWessels, Len
dc.contributor.authorNeefjes, Jen
dc.contributor.authorStål, Oen
dc.contributor.authorLinn, Sen
dc.contributor.authorLandberg, Göranen
dc.contributor.authorMichalides, Ren
dc.date.accessioned2011-01-24T10:28:42Z
dc.date.available2011-01-24T10:28:42Z
dc.date.issued2011-01
dc.identifier.citationPKA-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 Treaten
dc.identifier.issn1573-7217
dc.identifier.pmid20213082
dc.identifier.doi10.1007/s10549-010-0798-y
dc.identifier.urihttp://hdl.handle.net/10541/120246
dc.description.abstractPhosphorylation 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.
dc.language.isoenen
dc.subjectPKAen
dc.subjectPhosphorylationen
dc.subjectBreast Canceren
dc.subjectTamoxifenen
dc.titlePKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.en
dc.identifier.journalBreast Cancer Research and Treatmenten
html.description.abstractPhosphorylation 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.


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