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Open Access Highly Accessed Research article

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

Elin Karlsson1*, Gizeh Pérez-Tenorio1, Risul Amin1, Josefine Bostner1, Lambert Skoog2, Tommy Fornander3, Dennis C Sgroi4, Bo Nordenskjöld1, Anna-Lotta Hallbeck1 and Olle Stål1

Author Affiliations

1 Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, County Council of Östergötland, Linköping, SE-58185, Sweden

2 Department of Pathology and Cytology, Karolinska University Hospital, Solna, Stockholm, SE-17176, Sweden

3 Department of Oncology, Karolinska University Hospital, Stockholm South General Hospital, Stockholm, SE-11883, Sweden

4 Department of Pathology, Molecular Pathology Research Unit, Massachusetts General Hospital, Boston, MA, 02129, USA

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Breast Cancer Research 2013, 15:R96  doi:10.1186/bcr3557

Published: 17 October 2013

Abstract

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.