Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer

// Meng-Lay Lin 1, * , Hetal Patel 1, * , Judit Remenyi 2 , Christopher R. S. Banerji 3, 4 , Chun-Fui Lai 1 , Manikandan Periyasamy 1 , Ylenia Lombardo 1 , Claudia Busonero 1 , Silvia Ottaviani 1 , Alun Passey 1 , Philip R. Quinlan 5 , Colin A. Purdie 5 , Lee B. Jordan 5 , Alastair M. Thompson 6 , Richard S. Finn 7 , Oscar M. Rueda 8 , Carlos Caldas 8 , Jesus Gil 9 , R. Charles Coombes 1 , Frances V. Fuller-Pace 2 , Andrew E. Teschendorff 3, 4 , Laki Buluwela 1 , Simak Ali 1 1 Department of Surgery & Cancer, Imperial College London, London, UK 2 Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK 3 Statistical Genomics Group, UCL Cancer Institute, University College London, London, UK 4 Centre of Mathematics and Physics in Life & Experimental Sciences, University College London, UK 5 Dundee Cancer Centre, Clinical Research Centre, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK 6 Department of Surgical Oncology, MD Anderson Cancer Center, Houston, USA 7 Geffen School of Medicine at UCLA, Los Angeles, CA USA 8 Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge, UK 9 Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK * These authors have contributed equally to this work Correspondence to: Simak Ali, e-mail: simak.ali@imperial.ac.uk Keywords: cancer, nuclear receptors, expression profiling, breast cancer, tumour classification Received: March 11, 2015      Accepted: April 30, 2015      Published: May 13, 2015 ABSTRACT The Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.