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Bostner, Josefine
Publications (10 of 13) Show all publications
Manna, S., Bostner, J., Sun, Y., Miller, L. D., Alayev, A., Schwartz, N. S., . . . Holz, M. K. (2016). ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.. Clinical Cancer Research, 22(6), 1421-1431
Open this publication in new window or tab >>ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer.
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 6, p. 1421-1431Article in journal (Refereed) Published
Abstract [en]

PURPOSE: 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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125928 (URN)10.1158/1078-0432.CCR-15-0857 (DOI)000373358900018 ()26542058 (PubMedID)
Note

Funding agencies:  NIH [CA151112, HL098216]; Atol Charitable Trust; American Cancer Society [RSG-13-287-01-TBE]; National Cancer Center; Yeshiva University; Swedish Cancer Society

Available from: 2016-03-09 Created: 2016-03-09 Last updated: 2018-03-21
Karlsson, E., Magic, I., Bostner, J., Dyrager, C., Lysholm, F., Hallbeck, A.-L., . . . Lundström, P. (2015). Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis. PLoS ONE, 10(12), e0145013
Open this publication in new window or tab >>Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, p. e0145013-Article in journal (Refereed) Published
Abstract [en]

Background

The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.

Materials and methods

Whole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.

Results

Genome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.

Place, publisher, year, edition, pages
Public Library Science, 2015
National Category
Clinical Medicine Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-124494 (URN)10.1371/journal.pone.0145013 (DOI)000367092600042 ()26698305 (PubMedID)
Note

At the time for thesis presentation publication was in status: Manuscript

Funding Agencies|Swedish Research Council [2012-5136, 2007-3475]; Swedish Cancer Foundation; LiU Cancer; LiU Cancer Foundation

Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30Bibliographically approved
Bostner, J., Karlsson, E., Bivik Eding, C., Perez-Tenorio, G., Franzén, H., Konstantinell, A., . . . Stål, O. (2015). S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts. Endocrine-Related Cancer, 22(3), 331-343
Open this publication in new window or tab >>S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts
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2015 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 3, p. 331-343Article in journal (Refereed) Published
Abstract [en]

Detection 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.

Place, publisher, year, edition, pages
BioScientifica, 2015
Keywords
pS6K; S6K1; S6K2; mTOR; AKT; estrogen receptor; endocrine treatment
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120883 (URN)10.1530/ERC-14-0513 (DOI)000359003500016 ()25972244 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Ostergotland County Council; Lions Research Fund

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04
Aguilar, H., Urruticoechea, A., Halonen, P., Kiyotani, K., Mushiroda, T., Barril, X., . . . Pujana, M. A. (2014). VAV3 mediates resistance to breast cancer endocrine therapy. Breast Cancer Research, 16(3), R53
Open this publication in new window or tab >>VAV3 mediates resistance to breast cancer endocrine therapy
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2014 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 16, no 3, p. R53-Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.

METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.

RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.

CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-107051 (URN)10.1186/bcr3664 (DOI)000349083900009 ()24886537 (PubMedID)
Note

We wish to thank all study participants and their clinicians for their valuable contributions. This work was supported by grants from the Eugenio Rodriguez Pascual Foundation (2012, to MAP), the Government of Catalonia (2009-SGR283, to AV and MAP), the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01 DK015556, to JAK), the Red Cooperative Research Thematic Network on Cancer (RTICC) (12/0036/0002 to XRB and 12/0036/0008 to XRB and MAP) and the Spanish Ministry of Health, Fund for Health Research-Institute of Health Carlos III (11/00951 to AU and 12/01528 to MAP).

Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2017-12-05Bibliographically approved
Bostner, J., Karlsson, E., Pandiyan, M. J., Westman, H., Skoog, L., Fornander, T., . . . Stål, O. (2013). Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Research and Treatment, 137(2), 397-406
Open this publication in new window or tab >>Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit
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2013 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 137, no 2, p. 397-406Article in journal (Refereed) Published
Abstract [en]

The 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.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
mTOR, Akt, Estrogen receptor phosphorylation, Tamoxifen resistance, Immunohistochemistry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88458 (URN)10.1007/s10549-012-2376-y (DOI)000313201100007 ()
Note

Funding Agencies|Swedish Cancer Society||Swedish Research Council||King Gustaf V Jubilee Fund||

Available from: 2013-02-07 Created: 2013-02-07 Last updated: 2017-12-06
Bostner, J., Karlsson, E., Bivik, C., Perez-Tenorio, G., Franzén, H., Konstantinell, A., . . . Stål, O. (2013). S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts.
Open this publication in new window or tab >>S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. A simultaneous knockdown of the S6Ks in ER-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6K1+S6K2 dependent, suggesting separate roles in proliferation and in tamoxifen response. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.

In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity andintracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely tobenefit from tamoxifen and thus in need of an alternative or additional treatment.

Keywords
pS6K, S6K1, S6K2, mTOR, Akt, estrogen receptor, endocrine treatment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100902 (URN)
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-11-14Bibliographically approved
Bostner, J. (2013). The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations: a crosstalk with potential to predict tamoxifen resistance in breast cancer. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations: a crosstalk with potential to predict tamoxifen resistance in breast cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Estrogen receptor α content is the primary breast cancer biomarker distinguishing the patients responsive from the non-responsive to endocrine treatments. Tamoxifen is an estrogen competitor with large potential to treat breast cancer patients and prolongs time to recurrence. Despite the estrogen receptor positivity and tamoxifen treatment, many women face recurrence of the disease. An important mechanism of resistance to endocrine treatments is upregulated growth factor signaling, and the subsequent effect on the estrogen receptor, rendering an active receptor that stimulates cell proliferation or reduced estrogen-receptor dependence.

This thesis concerns the investigation of biomarkers, as a complement to the existing markers, for determining optimal treatment for patients with primary invasive breast cancer. Randomized patient tumor materials were used in order to measure variations in gene copies, proteins, and protein phosphorylations and to further relate these variations to time-to-recurrence. Endocrine untreated groups within the patient tumor sets gave us the opportunity to study the prognostic potential of selected markers and to compare tamoxifen-treated patients with endocrine untreated, thus obtaining a treatment-predictive value of each marker or marker combination.

In endocrine-dependent cancer the 11q13 chromosomal region is frequently amplified, harboring the genes encoding the cell cycle stimulator cyclin D1 and the estrogen receptor phosphorylating kinase Pak1, respectively. Amplification of the genes was associated with reduced time-torecurrence, indicating a prognostic value, whereas PAK1 gene amplification predicted reduced response to tamoxifen treatment. Moreover, the protein expression of Pak1 tended to predict treatment response, which led to the investigation of this protein in a larger cohort. Together with one of its targets, the estrogen receptor phosphorylation at serine 305, Pak1 predicted reduced response to tamoxifen treatment when detected in the nucleus of tumor cells, suggesting activation of this pathway as a mechanism for tamoxifen-treatment resistance. The estrogen receptor is phosphorylated by several growth factor stimulated kinases. The role of serine-167 phosphorylation has been debated, with inconsistent results. To study the biomarker value of this site the upstream activity of Akt, mTOR, and the S6 kinases were analyzed individually and in combinations. As a prognostic factor, serine 167 indicated an improved breast cancer survival, and as a treatment predictive factor we could not detect a significant value of serine 167 as a single marker. However, in combination with serine 305, and Akt/mTOR-pathway activation, the response to tamoxifen treatment was reduced. The mTOR effector protein S6K1 was found to be associated with HER2 positivity and a worse prognosis. In the group of patients with S6K1 accumulation in the tumor cell nuclei, treatment did not prolong time-to-recurrence, similarly as observed with expression of active S6 kinases. In vitro, a simultaneous knockdown of the S6 kinases in estrogen receptor-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6 kinase dependent.

The results presented herein suggest biomarkers that would improve treatment decisions in the clinic, specifically for estrogen receptor-positive breast cancer and tamoxifen treatment but in a broader perspective, also for other endocrine treatments and targeted treatments.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. p. 71
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1379
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100903 (URN)10.3384/diss.diva-100903 (DOI)978-91-7519-515-5 (ISBN)
Public defence
2013-12-18, Nils-Holgersalen, ing. 71, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-12-12Bibliographically approved
Karlsson, E., Pérez-Tenorio, G., Amin, R., Bostner, J., Skoog, L., Fornander, T., . . . Stål, O. (2013). The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.. Breast Cancer Research, 15(5), R96
Open this publication in new window or tab >>The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.
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2013 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, no 5, p. R96-Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keywords
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-104178 (URN)10.1186/bcr3557 (DOI)000329763800024 ()24131622 (PubMedID)
Available from: 2014-02-10 Created: 2014-02-10 Last updated: 2017-12-06Bibliographically approved
Karlsson, E., Ahnström, M., Bostner, J., Perez-Tenorio, G., Olsson, B., Hallbeck, A.-L. & Stål, O. (2011). High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP1. Genes, Chromosomes and Cancer, 50(10), 775-787
Open this publication in new window or tab >>High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP1
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2011 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, no 10, p. 775-787Article in journal (Refereed) Published
Abstract [en]

The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [ RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70514 (URN)10.1002/gcc.20900 (DOI)000294177300003 ()
Note

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||

Available from: 2011-09-12 Created: 2011-09-12 Last updated: 2017-12-08
Bostner, J., Skoog, L., Fornander, T., Nordenskjöld, B. & Stål, O. (2010). Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer. Clinical Cancer Research, 16(5), 1624-1633
Open this publication in new window or tab >>Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 5, p. 1624-1633Article in journal (Refereed) Published
Abstract [en]

Purpose: 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.

Place, publisher, year, edition, pages
American Association for Cancer Research, Inc., 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58377 (URN)10.1158/1078-0432.CCR-09-1733 (DOI)000278545500030 ()
Note
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-09-1733 Copyright: American Association for Cancer Research, Inc. http://www.aacr.org/ Available from: 2010-08-13 Created: 2010-08-11 Last updated: 2017-12-12
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