Research Article ZNF703 in luminal B breast cancer ZNF703 gene amplification at 8p12 specifies luminal B breast cancer Fabrice Sircoulomb1y, Nathalie Nicolas1, Anthony Ferrari1z, Pascal Finetti1, Ismahane Bekhouche 1 , Estelle Rousselet1x, Aur´elie Lonigro1xx, Jos´e Ad´ela¨ıde 1 , Emilie Baudelet2, S´everine Esteyri`es1k, Julien Wicinski1, St´ephane Audebert2, Emmanuelle Charafe-Jauffret1,3,4, Jocelyne Jacquemier1,3, Marc Lopez1, Jean-Paul Borg2,4, Christos Sotiriou 5 , Cornel Popovici1,4 , Franc¸ois Bertucci1,4,6, Daniel Birnbaum1, Max Chaffanet1*,#, Christophe Ginestier1**,# Keywords: 8p11 amplification; breast cancer; cancer stem cell; luminal B; ZNF703 DOI 10.1002/emmm.201100121 Received June 24, 2010 Revised January 13, 2011 Accepted January 14, 2011 GSee accompanying Closeup by Vessela Kristensen DOI 10.1002/emmm201100128 Luminal B breast cancers represent a fraction of oestrogen receptor (ER)-positive tumours associated with poor recurrence-free and disease-speciﬁc survival in all adjuvant systemic treatment categories including hormone therapy alone. Identi- ﬁcation of speciﬁc signalling pathways driving luminal B biology is paramount to improve treatment. We have studied 100 luminal breast tumours by combined analysis of genome copy number aberrations and gene expression. We show that ampliﬁcation of the ZNF703 gene, located in chromosomal region 8p12, prefer- entially occurs in luminal B tumours. We explored the functional role of ZNF703 in luminal B tumours by overexpressing ZNF703 in the MCF7 luminal cell line. Using mass spectrometry, we identiﬁed ZNF703 as a co-factor of a nuclear complex comprising DCAF7, PHB2 and NCOR2. ZNF703 expression results in the activation of stem cell-related gene expression leading to an increase in cancer stem cells. Moreover, we show that ZNF703 is implicated in the regulation of ER and E2F1 transcription factor. These ﬁndings point out the prominent role of ZNF703 in transcription modulation, stem cell regulation and luminal B oncogenesis. (1) Laboratoire d’Oncologie Mol´eculaire, Centre de Recherche en Canc´erologie de Marseille, Inserm, U891, Institut Paoli-Calmettes, Marseille, France. (2) D´epartement de Pharmacologie Mol´eculaire, Centre de Recherche en Canc´erologie de Marseille, Institut Paoli-Calmettes, Marseille, France. (3) D´epartement de BioPathologie, Institut Paoli-Calmettes, Marseille, France. (4) Universit´e de la M´editerran´ee, Marseille, France. (5) Institut Jules Bordet, Bruxelles, Belgique. (6) D´epartement d’Oncologie M´edicale, Institut Paoli-Calmettes, Marseille, France. *Corresponding author: Tel: þ33 4 91 22 34 77; Fax: þ33 4 91 22 35 44 E-mail: chaffanetm@marseille.fnclcc.fr **Corresponding author: Tel: þ33 4 91 22 35 09; Fax: þ33 4 91 22 35 44 E-mail: christophe.ginestier@inserm.fr y Present address: MaRS Centre Toronto Medical Discovery district, Toronto, Ontario, Canada z Present address: Fondation Synergie Lyon Cancer, Centre L´eon B´erard, Lyon, France x Present address: Texas Tech University, Lubbock, Texas, USA xx Present address: Facult´e de M´edecine, CRN2M, UMR6231, IFR Jean Roche, Secteur Nord, Universit´e de la M´editerran´ee, Marseille, France k Present address: Unit´e de Pharmacologie Clinique Exp´erimentale et Th´erapeutique, CHU La Timone, Marseille, France Present address: G´en´etique M´edicale, Hˆopital de la Timone, Marseille, France #Contributed equally. INTRODUCTION Despite improvements in the treatment of breast cancer, resistance to therapy is a major clinical problem. The molecular taxonomy of breast cancer based on transcriptional proﬁling has led to a better classiﬁcation of tumours and pointed out new potential therapeutic targets. Breast cancers are classiﬁed into ﬁve molecular subtypes: luminal A, luminal B, basal, ERBB2-like and normal-like (Sorlie et al, 2001, 2003). Molecular subtypes are associated with various clinical outcomes, and treatment strategies are tailored to corresponding groups of patients (e.g. anti-ERBB2 therapies for patients with ERBB2-like tumours or hormone therapy for patients with luminal tumours). Although both luminal A and B tumours express hormone receptors (oestrogen and progesterone), the risk of relapse in women treated by hormone therapy is greater in women with a luminal B tumour than in women with a luminal A tumour. Moreover, luminal B tumours are associated with poor disease-speciﬁc survival when treated with chemotherapy (Cheang et al, 2009). Therefore, the elucidation of the molecular mechanisms that govern luminal B tumour biology should improve both our understanding of tumourigenesis and treatment of patients. www.embomolmed.org EMBO Mol Med 3, 153–166 2011 EMBO Molecular Medicine 153