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Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients
Caroline Holm1, Suresh Rayala, Karin Jirström
1Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö, Sweden.
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 (ERalpha) 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 ERalpha 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 (Pak1DeltaNLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ERalpha 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 ERalpha-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 Pak1DeltaNLS, 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 ERalpha signaling and in tamoxifen resistance.
Insights
p21-activated kinase 1 (Pak1) nuclear localization is linked to tamoxifen resistance in breast cancer. Lower Pak1 expression in ERalpha-positive tumors improves tamoxifen treatment outcomes, highlighting Pak1 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- p21-activated kinase 1 (Pak1) is a key regulator of cellular processes, phosphorylating numerous proteins.
- Pak1's activation of estrogen receptor alpha (ERalpha) may impede antiestrogen therapies for breast cancer.
- Investigating Pak1's role in tamoxifen resistance is crucial for improving breast cancer treatment.
Purpose of the Study:
- To examine the association between Pak1 expression, its subcellular localization, and tamoxifen resistance in breast cancer.
- To determine if Pak1 influences ERalpha activity and tamoxifen responsiveness in preclinical models.
Main Methods:
- Evaluated Pak1 protein expression in 403 primary breast tumors from premenopausal patients.
- Assessed tamoxifen response by comparing recurrence-free survival based on Pak1 and ERalpha levels.
- Utilized MCF-7 and Ishikawa cancer cell lines to investigate Pak1's impact on ERalpha signaling and tamoxifen sensitivity.
Main Results:
- Patients with ERalpha-positive tumors and low Pak1 expression showed improved recurrence-free survival with tamoxifen.
- High cytoplasmic or any nuclear Pak1 expression did not significantly alter recurrence-free survival between treatment groups.
- Overexpression of wild-type Pak1, but not a non-nuclear variant, reduced tamoxifen response in MCF-7 cells by increasing cyclin D1.
- Tamoxifen treatment increased nuclear Pak1 and its activity in Ishikawa cells, suggesting a regulatory feedback loop.
Conclusions:
- Pak1, particularly when localized in the nucleus, plays a significant role in ERalpha signaling.
- Pak1 is implicated as a mediator of tamoxifen resistance in breast cancer.
- Targeting nuclear Pak1 may represent a novel therapeutic strategy to overcome tamoxifen resistance.