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Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.

Wigerup, Caroline LU ; Rayala, Suresh; Jirström, Karin LU ; Stal, Olle; Kumar, Rakesh and Landberg, Göran LU (2006) In J Natl Cancer Inst 98(10). p.671-680
Abstract
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 alpha (ER alpha) 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 alpha expression in untreated versus tamoxifen-treated patients.... (More)
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 alpha (ER alpha) 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 alpha 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 Delta NLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ER alpha 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 alpha-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 Pak1 Delta NLS, 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 alpha signaling and in tamoxifen resistance. (Less)
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Predictive Value of Tests, Phosphorylation, Neoplasm Staging, Middle Aged, Hormonal: pharmacology, Antineoplastic Agents, Adult, Hormonal: therapeutic use, Blotting, Tumor, Cell Line, Breast Neoplasms: therapy, Breast Neoplasms: prevention & control, Breast Neoplasms: pathology, Breast Neoplasms: chemistry, Western, Disease-Free Survival, Neoplasm, Drug Resistance, Female, Estrogen Receptor alpha: metabolism, Estrogen Receptor alpha: drug effects, Estrogen Antagonists: therapeutic use, Estrogen Antagonists: pharmacology, Gene Expression Regulation, Follow-Up Studies, Microscopy, Immunohistochemistry, Humans, Neoplastic, Confocal, Fluorescence, Protein-Serine-Threonine Kinases: analysis, Randomized Controlled Trials, Research Support, N.I.H., Extramural, Non-U.S. Gov't, Tamoxifen: pharmacology, Tamoxifen: therapeutic use, Tumor Markers, Biological: analysis, Premenopause, Protein Array Analysis, Prognosis
in
J Natl Cancer Inst
volume
98
issue
10
pages
671 - 680
publisher
Oxford University Press
external identifiers
  • wos:000238390200008
  • pmid:16705121
  • scopus:33646940460
ISSN
1460-2105
DOI
10.1093/jnci/djj185
language
English
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yes
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9d3f801a-26bf-4357-aad7-9376c01a9447 (old id 156726)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16705121&dopt=Abstract
date added to LUP
2007-07-25 11:47:19
date last changed
2019-10-20 04:16:00
@article{9d3f801a-26bf-4357-aad7-9376c01a9447,
  abstract     = {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 alpha (ER alpha) 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 alpha 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 Delta NLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ER alpha 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 alpha-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 Pak1 Delta NLS, 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 alpha signaling and in tamoxifen resistance.},
  author       = {Wigerup, Caroline and Rayala, Suresh and Jirström, Karin and Stal, Olle and Kumar, Rakesh and Landberg, Göran},
  issn         = {1460-2105},
  keyword      = {Predictive Value of Tests,Phosphorylation,Neoplasm Staging,Middle Aged,Hormonal: pharmacology,Antineoplastic Agents,Adult,Hormonal: therapeutic use,Blotting,Tumor,Cell Line,Breast Neoplasms: therapy,Breast Neoplasms: prevention & control,Breast Neoplasms: pathology,Breast Neoplasms: chemistry,Western,Disease-Free Survival,Neoplasm,Drug Resistance,Female,Estrogen Receptor alpha: metabolism,Estrogen Receptor alpha: drug effects,Estrogen Antagonists: therapeutic use,Estrogen Antagonists: pharmacology,Gene Expression Regulation,Follow-Up Studies,Microscopy,Immunohistochemistry,Humans,Neoplastic,Confocal,Fluorescence,Protein-Serine-Threonine Kinases: analysis,Randomized Controlled Trials,Research Support,N.I.H.,Extramural,Non-U.S. Gov't,Tamoxifen: pharmacology,Tamoxifen: therapeutic use,Tumor Markers,Biological: analysis,Premenopause,Protein Array Analysis,Prognosis},
  language     = {eng},
  number       = {10},
  pages        = {671--680},
  publisher    = {Oxford University Press},
  series       = {J Natl Cancer Inst},
  title        = {Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.},
  url          = {http://dx.doi.org/10.1093/jnci/djj185},
  volume       = {98},
  year         = {2006},
}