Estrogen receptor-alpha phosphorylation at serine 305, nuclear p21-activated kinase 1 expression, and response to tamoxifen in postmenopausal breast cancer.
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.
Bostner
Josefine
J
Division of Surgery and Clinical Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden. josefine.bostner@liu.se
Skoog
Lambert
L
Fornander
Tommy
T
Nordenskjöld
Bo
B
Stål
Olle
O
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
D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D012694:Serine; D054462:p21-Activated Kinases