title: PKA-induced phosphorylation of ERα at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer.
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.
authors.affiliation: Department of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Kok
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Caroline
authors.initials: C
authors.lastname: Holm
authors.forename: Renske
authors.initials: R
authors.lastname: Fles
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Van't Veer
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Rob
authors.initials: R
authors.lastname: Michalides
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism*; D005060:Europe; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D018579:Patient Selection; D010766:Phosphorylation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D012694:Serine; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D046888:Tissue Array Analysis; D014162:Transfection; D016896:Treatment Outcome; D015854:Up-Regulation; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D012694:Serine; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases