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

Holm, Caroline; Rayala, Suresh K.; Jirström, Karin; Stål, Olle; Kumar, Rakesh; Landberg, Göran

doi:10.1093/jnci/djj185

Cited by 176 publications

(177 citation statements)

References 30 publications

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“…No correlation between pak1 staining intensity and S-phase fraction was found in this study. This is in contrast to results presented by Holm et al (2006), where both cytoplasmic and nuclear overexpression was associated with high expression of the proliferation marker Ki-67. Neither could any correlation between cyclin D1 staining intensity and proliferation be detected in our study (data not shown).…”

Section: Discussioncontrasting

confidence: 99%

“…Neither could any correlation between cyclin D1 staining intensity and proliferation be detected in our study (data not shown). In agreement with Holm et al (2006), we observed no link between pak1 overexpression and RFS in univariate analysis. Also in line with Holm et al (2006), patients with overexpressed pak1 show decreased response to tamoxifen.…”

Section: Discussionsupporting

confidence: 89%

“…Experimental studies have recently shown increasing evidence for the cyclin D1 and pak1 connection to tamoxifen response (Hodges et al, 2003;Holm et al, 2006;Rayala et al, 2006b). For that reason, we sought to analyse the association of these two genes with tamoxifen resistance in a clinical material.…”

Section: Discussionmentioning

confidence: 99%

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Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

et al. 2007

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The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (Po0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 89%

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Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

et al. 2007

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“…Activation of PAK1 results in actin phosphorylation in breast cancer cells, leading to a reorganisation of the cytoskeleton that favours cell migration and invasiveness (Adam et al, 1998). Activated PAK1 also phosphorylates and activates oestrogen receptor-a (ERa) independently of ligand stimulation, leading to increased Cyclin D1 expression and cell cycle progression (Holm et al, 2006). Mammary glands from catalytically active PAK1 transgenic mice exhibit hyperplasia (Balasenthil et al, 2004).…”

mentioning

confidence: 99%

“…Activation of PAK1 inhibits tamoxifen action in vitro and in animal models . Clinically, the overexpression and nuclear localisation of PAK1 are associated with tamoxifen resistance in a subset of ER-positive tumours (Holm et al, 2006).…”

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Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

et al. 2008

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The ErbB3 binding protein (Ebp1) is a transcriptional corepressor that inhibits the activity of proliferation-associated genes and the growth of human breast cancer cell lines. Treatment of breast cancer cells with the ErbB3 ligand heregulin (HRG) results in increased phosphorylation of Ebp1 and transcriptional repression. The p21-activated serine/threonine kinase 1 (PAK1), which plays an important role in breast cancer progression and resistance to the anti-oestrogen tamoxifen, is also activated by HRG. We therefore examined the ability of PAK1 to phosphorylate and regulate the function of Ebp1. We found that PAK1 phosphorylated Ebp1 in vitro and mapped the phosphorylation site to threonine 261. Both HRG treatment and expression of a constitutively activated PAK1 in MCF-7 breast cancer cells enhanced threonine phosphorylation of Ebp1. In MCF-7 cells, ectopically expressed Ebp1 bound endogenous PAK1 and this association was enhanced by treatment with HRG. Mutation of the PAK1 phosphorylation site to glutamic acid, mimicking a phosphorylated state, completely abrogated the ability of Ebp1 to repress transcription, inhibit growth of breast cancer cell lines and contribute to tamoxifen sensitivity. These studies demonstrate for the first time that Ebp1 is a substrate of PAK1 and the importance of the PAK1 phosphorylation site for the functional activity of Ebp1 in breast cancer cells.

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Kinases and Cancer

Matthews¹,

Gerritsen²

2010

Targeting Protein Kinases for Cancer Therapy

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

Abstract: Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance.

Cited by 176 publications

References 30 publications

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Kinases and Cancer

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