HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0076v1 42/2/87    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ghayad, S. Articles by Cohen, P. Search for Related Content PubMed PubMed Citation Articles by Ghayad, S. Articles by Cohen, P.

S Ghayad, Centre Leon Berard, FNCLCC, INSERM U590, Universite de Lyon, Lyon 1, ISPB, Faculte de Pharmacie de Lyon, Lyon, France
J Vendrell, Centre Leon Berard, FNCLCC, INSERM U590, Universite de Lyon, Lyon 1, ISPB, Faculte de Pharmacie de Lyon, Lyon, France
I Bieche, INSERM U735, Laboratoire d'Oncogenetique, St-Cloud, France
F Spyratos, INSERM U735, Laboratoire d'Oncogenetique, St-Cloud, France
C Dumontet, INSERM U590, Universite de Lyon, Lyon 1, Faculte de Medecine de Lyon, Lyon, France
I Treilleux, INSERMU590, Centre Leon Berard, FNCLCC, Lyon, France
R Lidereau, INSERM U735, Laboratoire d'Oncogenetique, St-Cloud, France
P Cohen, Centre Leon Berard, FNCLCC, INSERM U590, Universite de Lyon, Lyon 1, ISPB, Faculte de Pharmacie de Lyon, Lyon, France

Correspondence: Pascale Cohen, Email: PASCALE.COHEN{at}recherche.univ-lyon1.fr

Abstract

Cross-resistance to molecules used in endocrine therapy is among the main challenges in the treatment of estrogen receptor alpha (ER) positive breast cancer. In this study, we used two different cell models of resistance to anti-estrogens: MVLN/CL6.7 cells and VP229/VP267 cells selected after exposure to tamoxifen, respectively in vitro and in vivo to characterize a phenotype rarely observed, i.e. acquisition of cross-resistance to the pure ER antagonist fulvestrant. As MVLN/CL6.7 cells and VP229/VP267 cell lines are original and valuable models of cross-resistance to tamoxifen and fulvestrant, we examined candidate genes using a RTQ-PCR strategy to identify new biomarkers of endocrine resistance. Of the 26 candidate genes tested, 19 displayed deregulation of expression at the basal level in at least one of the two resistant cell lines. Eight genes (TACC1, NOV, PTTG1, MAD2L1, BAK1, TGFB2, BIRC5 and CCNE2) were significantly over-expressed in samples from ER-positive breast cancer patients who relapsed after tamoxifen treatment (n=24) compared to samples from patients who did not (n=24). Five genes (TACC1, NOV, PTTG1, BAK1 and TGFB2) were correlated with significantly shorter relapse-free survival (univariate analysis). Finally, we identified TACC1 and a three-gene expression signature (TACC1, NOV and PTTG1) as independent prognostic markers (multivariate analysis). Aberrant mRNA and protein levels of TACC1, NOV and PTTG1 were also observed under tamoxifen and/or fulvestrant exposure in resistant CL6.7 cells compared to their respective control MVLN cells. In conclusion, our data identify TACC1, NOV and PTTG1 as promising new markers that could be used in the clinical management of ER-positive breast cancer patients.