Association Between Pak1 Expression and Subcellular Localization and Tamoxifen Resistance in Breast Cancer Patients

• DOI: 10.1093/jnci/djj185
• Publication Date: 2006-05-16T20:47:43Z
• Authors: Caroline Holm; Suresh Rayala; Karin Jirström; Olle Stål; Rakesh Kumar; Göran Landberg
• Keywords: PAK1; Antiestrogen

p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate thereby activate the estrogen receptor alpha (ERalpha) potentially limits effectiveness of antiestrogen treatment breast cancer. Here we studied associations between Pak1 expression subcellular localization tumor cells tamoxifen resistance.Pak1 protein was evaluated 403 primary tumors from premenopausal patients who had been randomly assigned 2 years adjuvant or no treatment. Tamoxifen response by comparing recurrence-free survival relation ERalpha untreated versus tamoxifen-treated patients. responsiveness human MCF-7 cancer that inducibly expressed constitutively active transiently overexpressed wild-type (Wt-Pak1) lacked functional nuclear signals (Pak1DeltaNLS) analyzing cyclin D1 promoter activation levels as markers for activation. The analyzed naturally tamoxifen-resistant Ishikawa endometrial All statistical tests were two-sided.Among ERalpha-positive with low expression, those treated better than received (hazard ratio [HR] = 0.502, 95% confidence interval [CI] 0.331 0.762; P .001) whereas there difference groups whose high cytoplasmic (HR 0.893, CI 0.420 1.901; .769) any 0.955, 0.405 2.250; .916). In cells, overexpression Wt-Pak1, but not Pak1DeltaNLS, compromised stimulating expression. Treatment led an increase amount activity, suggesting tamoxifen, some extent, regulates expression.Our data support a role Pak1, particular localized nucleus, signaling resistance.