Research article
A candidate molecular signature associated with tamoxifen failure in primary breast cancer
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* Corresponding author: Pascale A Cohen pascale.cohen@recherche.univ-lyon1.fr
- † Equal contributors
1 Université de Lyon, 69008 Lyon, France
2 Université de Lyon, Lyon 1, ISPB, Faculté de Pharmacie de Lyon, 69008 Lyon, France
3 INSERM, U590, 69008 Lyon, France
4 Centre Léon Bérard, FNCLCC, 69373 Lyon, France
5 Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
6 CNRS UMR 5160, Centre de Pharmacologie et Biotechnologie pour la Santé, Faculté de Pharmacie, 34090 Montpellier, France
7 Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
8 Centre de Biochimie Structurale, CNRS, INSERM, Université Montpellier I, 34090 Montpellier, France
9 Centre Léon Bérard, FNCLCC, Unité de Biostatistique et d'Evaluation des Thérapeutiques, 69373 Lyon, France
10 INSERM ERM206, Laboratoire TAGC, Université d'Aix-Marseille II, 13288 Marseille Cedex 9, France
11 INSERM U735, Centre René Huguenin, FNCLCC, 92210 St-Cloud, France
12 Centre Léon Bérard, FNCLCC, Département de Médecine, 69373 Lyon, France
Breast Cancer Research 2008, 10:R88 doi:10.1186/bcr2158
Published: 17 October 2008Abstract
Introduction
Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.
Methods
Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.
Results
Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERα, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-α, γ-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERα, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERα, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERα alone (likelihood ratio test).
Conclusions
We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.