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© The Author 2006. Published by Oxford University Press.
ARTICLE |
Association Between Pak1 Expression and Subcellular Localization and Tamoxifen Resistance in Breast Cancer Patients
Affiliations of authors: Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden (CH, KJ, GL); Department of Oncology, University Hospital, Linköping, Sweden (OS); Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (SR, RK)
Correspondence to: Göran Landberg, MD, PhD, Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02, Malmö, Sweden (e-mail: goran.landberg{at}med.lu.se).
Background: p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate and thereby activate the estrogen receptor 
(ER) potentially limits the effectiveness of antiestrogen treatment in breast cancer. Here we studied associations between Pak1 expression and subcellular localization in tumor cells and tamoxifen resistance. Methods: Pak1 protein expression was evaluated in 403 primary breast tumors from premenopausal patients who had been randomly assigned to 2 years of adjuvant tamoxifen or no treatment. Tamoxifen response was evaluated by comparing recurrence-free survival in relation to Pak1 and ER expression in untreated versus tamoxifen-treated patients. Tamoxifen responsiveness of human MCF-7 breast cancer cells that inducibly expressed constitutively active Pak1 or that transiently overexpressed wild-type Pak1 (Wt-Pak1) or Pak1 that lacked functional nuclear localization signals (Pak1
NLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ER activation. The response to tamoxifen in relation to Pak1 expression was analyzed in naturally tamoxifen-resistant Ishikawa human endometrial cancer cells. All statistical tests were two-sided. Results: Among patients who had ER–positive tumors with low Pak1 expression, those treated with tamoxifen had better recurrence-free survival than those who received no treatment (hazard ratio [HR] = 0.502, 95% confidence interval [CI] = 0.331 to 0.762; P = .001) whereas there was no difference in recurrence-free survival between treatment groups for patients whose tumors had high cytoplasmic (HR = 0.893, 95% CI = 0.420 to 1.901; P = .769) or any nuclear Pak1 expression (HR = 0.955, 95% CI = 0.405 to 2.250; P = .916). In MCF-7 cells, overexpression of Wt-Pak1, but not of Pak1NLS, compromised tamoxifen response by stimulating cyclin D1 expression. Treatment of Ishikawa cells with tamoxifen led to an increase in the amount of nuclear Pak1 and Pak1 kinase activity, suggesting that tamoxifen, to some extent, regulates Pak1 expression. Conclusions: Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ER signaling and in tamoxifen resistance.
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Editorial about this Article
- Pak up Your Breast Tumor—and Grow!
- V. Craig Jordan
J Natl Cancer Inst 2006 98: 657-659.[Extract] [Full Text] [PDF]
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