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Pérez-Tenorio, Gizeh
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Publications (10 of 21) Show all publications
Ellegård, S., Veenstra, C., Pérez-Tenorio, G., Fagerström, V., Garsjo, J., Gert, K., . . . Stål, O. (2019). ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab. Oncology Letters, 17(3), 3371-3381
Open this publication in new window or tab >>ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab
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2019 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, no 3, p. 3371-3381Article in journal (Refereed) Published
Abstract [en]

Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

Place, publisher, year, edition, pages
Athens, Greece: Spandidos Publications, 2019
Keywords
HER2; brain metastasis; protein tyrosine phosphatase non-receptor type 2; ribosomal protein S6 kinase B1; PI3K; phosphatase and tensin homolog
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-155540 (URN)10.3892/ol.2019.9998 (DOI)000460555900098 ()30867772 (PubMedID)2-s2.0-85062153648 (Scopus ID)
Note

Funding Agencies|Swedish Cancer Society [17-0479]; Medical Research Council of Southeast Sweden [FORSS-757671]; ALF Grants Region Ostergotland [LIO-795201]; Stiftelsen Onkologiska Klinikernas Forskningsfond i Linkoping [2016-06-21]

Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-08-27Bibliographically approved
Husa, A.-M., Magic, Z., Larsson, M., Fornander, T. & Perez-Tenorio, G. (2016). EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer. OncoTarget, 7(16), 21362-21380
Open this publication in new window or tab >>EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 16, p. 21362-21380Article in journal (Refereed) Published
Abstract [en]

The EPH and ephrins function as both receptor and ligands and the output on their complex signaling is currently investigated in cancer. Previous work shows that some EPH family members have clinical value in breast cancer, suggesting that this family could be a source of novel clinical targets. Here we quantified the mRNA expression levels of EPH receptors and their ligands, ephrins, in 65 node positive breast cancer samples by RT-PCR with TaqMan (R) Micro Fluidics Cards Microarray. Upon hierarchical clustering of the mRNA expression levels, we identified a subgroup of patients with high expression, and poor clinical outcome. EPHA2, EPHA4, EFNB1, EFNB2, EPHB2 and EPHB6 were significantly correlated with the cluster groups and particularly EPHB2 was an independent prognostic factor in multivariate analysis and in four public databases. The EPHB2 protein expression was also analyzed by immunohistochemistry in paraffin embedded material (cohort 2). EPHB2 was detected in the membrane and cytoplasmic cell compartments and there was an inverse correlation between membranous and cytoplasmic EPHB2. Membranous EPHB2 predicted longer breast cancer survival in both univariate and multivariate analysis while cytoplasmic EPHB2 indicated shorter breast cancer survival in univariate analysis. Concluding: the EPH/EFN cluster analysis revealed that high EPH/EFN mRNA expression is an independent prognostic factor for poor survival. Especially EPHB2 predicted poor breast cancer survival in several materials and EPHB2 protein expression has also prognostic value depending on cell localization.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2016
Keywords
EPHB2; EPH family; TaqMan array; gene expression; protein expression
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130143 (URN)10.18632/oncotarget.7246 (DOI)000377705900023 ()26870995 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Stockholm Cancer Society; Oncology Clinics Research Fund of Linkoping

Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2018-03-20
Veenstra, C., Perez-Tenorio, G., Stelling, A., Karlsson, E., Mirwani Mirwani, S., Nordenskjöld, B., . . . Stål, O. (2016). Met and its ligand HGF are associated with clinical outcome in breast cancer. OncoTarget, 7(24), 37145-37159
Open this publication in new window or tab >>Met and its ligand HGF are associated with clinical outcome in breast cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 37145-37159Article in journal (Refereed) Published
Abstract [en]

Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo-or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre-and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the premenopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2016
Keywords
radiation; copy number variation; droplet digital PCR; triple-negative breast cancer; radiotherapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130130 (URN)10.18632/oncotarget.9268 (DOI)000377756800127 ()27175600 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; LiU Cancer Foundation

Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2019-06-28
Karlsson, E., Veenstra, C., Emin, S., Dutta, C., Perez-Tenorio, G., Nordenskjöld, B., . . . Stål, O. (2015). Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Research and Treatment, 153(1), 31-40
Open this publication in new window or tab >>Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer
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2015 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 153, no 1, p. 31-40Article in journal (Refereed) Published
Abstract [en]

Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2015
Keywords
18p; AKT; Breast cancer; Endocrine resistance; Phosphatases; PTPN2
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121133 (URN)10.1007/s10549-015-3516-y (DOI)000359775100005 ()26208487 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [13 0435]; Swedish Research Council [A0346701]

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2019-06-28
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
Fohlin, H., Perez-Tenorio, G., Fornander, T., Skoog, L., Nordenskjöld, B., Carstensen, J. & Stål, O. (2013). Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer. European Journal of Cancer, 49(6), 1196-1204
Open this publication in new window or tab >>Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer
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2013 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, no 6, p. 1196-1204Article in journal (Refereed) Published
Abstract [en]

Introduction

Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.

Material and methods

The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.

Results

The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.

Conclusion

Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Breast cancer, Akt, Protein kinase B, Oestrogen receptor, Long-term, Prognostic factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-92610 (URN)10.1016/j.ejca.2012.12.006 (DOI)000317188600005 ()
Note

Funding Agencies|Swedish Cancer Society||Swedish Research Council||

Available from: 2013-05-16 Created: 2013-05-14 Last updated: 2018-02-28
Falivelli, G., Lisabeth, E. M., Rubio de la Torre, E., Perez-Tenorio, G., Tosato, G., Salvucci, O. & Pasquale, E. B. (2013). Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands. PLoS ONE, 8(11), e81445
Open this publication in new window or tab >>Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e81445-Article in journal (Refereed) Published
Abstract [en]

The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans.

Place, publisher, year, edition, pages
San Francisco, CA, United States: Public Library of Science, 2013
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107050 (URN)10.1371/journal.pone.0081445 (DOI)000327670300032 ()24348920 (PubMedID)2-s2.0-84896715497 (Scopus ID)
Available from: 2014-06-04 Created: 2014-06-04 Last updated: 2018-01-11Bibliographically approved
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
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
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