13 research outputs found
Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
No full textPurpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy. Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment. Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P less than 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment. Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.Original Publication:Josefine Bostner, Lambert Skoog, Tommy Fornander, Bo Nordenskjöld and Olle Stål, Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer, 2010, Clinical Cancer Research, (16), 5, 1624-1633.http://dx.doi.org/10.1158/1078-0432.CCR-09-1733Copyright: American Association for Cancer Research, Inc.http://www.aacr.org
Estrogen Receptor α Phosphorylation on Serine 305, p21-Activated Kinase 1 and Tamoxifen Response in Postmenopausal Breast Cancer.
No full textAbstract
Background: Tamoxifen is an adjuvant treatment for estrogen receptor (ER) positive breast cancer. Despite high response rates, resistance is a widespread problem. p21-activated kinase 1 (Pak1) is suggested to phosphorylate the serine 305 residue of the ERα and influence the response to tamoxifen. We aimed to investigate the combination of Pak1 and pERαser305 in relation to treatment prediction and prognosis.Material and Methods: We examined Pak1 and pERαser305 protein by immunohistochemistry in a series of 912 tumors from node negative postmenopausal breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity while nuclear Pak1 and pERαser305 correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pERαser305 predicted reduced response to tamoxifen in patients with ERα-positive tumors (tamoxifen versus no tamoxifen, HR=1.33; 95% CI, 0.42-4.2, p=0.63), whereas patients lacking this combination of protein expression in the tumor benefitted significantly from tamoxifen (HR=0.42; 95% CI, 0.29-0.61; p<0.0001). Similar non-significant trends were detected in analyses of the two proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR=1.80; 95% CI, 1.18-2.76, p=0.006) and breast cancer mortality (HR=2.02; 95% CI, 1.16-3.52, p=0.014) for patients randomized to no adjuvant treatment.Discussion: Our results suggest that patients with tumors expressing nuclear Pak1 and nuclear pERαser305 in combination represent a subgroup in which tamoxifen treatment is insufficient. Our findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus. In addition, the Pak1-ER pathway may be of interest as drug target in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2013.</jats:p
Amplification of <i>CCND1</i> and <i>PAK1</i> as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer
No full textComprehensive Genomic and Transcriptomic Analysis of the 11q13 Amplicon in Breast Cancer.
No full textAbstract
Background: The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event associated with ER positive status but also implicated in resistance to endocrine therapies. Coamplifications of the 11q13 and 8p12 regions are commonly occurring, suggesting a synergy between genes in the amplicons. The present aim was to perform a comprehensive analysis of breast tumours harbouring amplification in the 11q13 region, and identify candidate oncogenes in the amplicon based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 connection was evaluated at the mRNA level, as well as its prognostic significance.Methods/materials: Affymetrix 250K Nsp SNP arrays were used for whole genome screening of DNA copy number changes in 29 breast tumours, assumed to be representative for the majority of 11q13 amplified cases in a patient material consisting of 200 postmenopausal women with stage II breast tumours. To identify regions of significant aberrations at 11q13 and 8p12 across all tumours, the principles of a statistical approach called Genomic Identification of Significant Targets in Cancer (GISTIC) was applied. mRNA expression levels of candidate oncogenes in respective amplicon (RAD9A, RPS6KB2, CCND1, FGF19, PAK1, GAB2 (11q13); EIF4EBP1, PPAPDC1B and FGFR1 (8p12) were evaluated using quantitative real-time PCR.Results: Resulting data revealed three main amplification cores at 11q13, centred on 66.9Mb, 69.1Mb and 77.0Mb. Loss of the distal part of 11q occurred in 97% (28/29) of the cases. With the exception for FGF19, a correlation between mRNA level and gene copy number was seen for all genes included in the study. ER expression was associated with the central 11q13 core, though no significant correlation to mRNA expression of included genes could be stated. Regarding the 8p12/11q13 connection, it was shown that DNA copy number, as well as mRNA-expression levels, significantly correlated between RPS6KB2 (core 66.9Mb, 11q13) and EIF4EBP1/PPAPDC1B (8p12). Amplification at 8p12 was significantly inversely correlated to 17q (HER2) amplification, whereas HER2 protein was significantly negatively correlated to PPAPDC1B mRNA-levels. High expression of RPS6KB2, EIF4EBP1 and FGFR1 was associated with a significant increased risk of distant recurrence in the patient group. Coexpression of RPS6KB2 and EIF4EBP1 was shown to predict a worse patient outcome compared to overexpression of only one of the genes, supporting earlier suggestions of a synergy between the 11q13 and 8p12 amplicons.Conclusions: The present study identifies three main amplification cores at 11q13 in breast tumours, with the most proximal correlated to 8p12 at both the genomic and the transcriptomic level. A clinical significance of RPS6KB2(11q13)/EIF4EBP1(8p12) coexpression/coamplification was indicated, but needs to be evaluated in larger patient cohorts.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5166.</jats:p
Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer
No full textDeregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ER alpha-positive cell lines was compared with that in ER alpha-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ER alpha signaling, here shown by a coupled increase of ER alpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ER alpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ER alpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ER alpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.Funding Agencies|Swedish Cancer Society; Region of Ostergotland; Cancer Society in Stockholm; King Gustav V Jubilee Clinical Research Foundation; National Cancer Institute (NCI); American Cancer Society; Atol Charitable Trust</p
Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit
No full textThe frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor alpha (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.</p
S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts
No full textDetection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, Pless than0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.Funding Agencies|Swedish Cancer Society; Swedish Research Council; Ostergotland County Council; Lions Research Fund</p
ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer
No full textPURPOSE: Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients.EXPERIMENTAL DESIGN: Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay.RESULTS: We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.CONCLUSION: Taken together, these data show that ERRα expression predicts response to tamoxifen treatment, and ERRα could be a biomarker of tamoxifen sensitivity and a prognostic factor in TNBC. Clin Cancer Res; 1-11. ©2015 AACR.</p
Supplementary Table 1 from ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer
No full textERRα protein expression and clinicopathological variables with respect to estrogen receptor (ER) and HER2 status.</p
