title: Estrogen receptor-alpha phosphorylation at serine 305, nuclear p21-activated kinase 1 expression, and response to tamoxifen in postmenopausal breast cancer.
abstract: OBJECTIVE
  In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ERalpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pERalpha(ser305) on breast cancer prognosis and results of tamoxifen therapy.
  
  
  METHODS
  We examined Pak1 and pERalpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.
  
  
  RESULTS
  Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pERalpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pERalpha(ser305) predicted reduced response to tamoxifen in patients with ERalpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P < 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment.
  
  
  CONCLUSIONS
  Our results suggest that patients with tumors expressing Pak1 and pERalpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.
authors.affiliation: Division of Surgery and Clinical Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden. josefine.bostner@liu.se
authors.forename: Josefine
authors.initials: J
authors.lastname: Bostner
authors.forename: Lambert
authors.initials: L
authors.lastname: Skoog
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010766:Phosphorylation; D017698:Postmenopause; D011379:Prognosis; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D012694:Serine / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis; D054462:p21-Activated Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D012694:Serine; D054462:p21-Activated Kinases