The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer
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Luca Magnani1, Darren K. Patten1, Van T.M. Nguyen1, Sung-Pil Hong1, Jennifer H. Steel1, Naina Patel1, Ylenia Lombardo1, Monica Faronato1, Ana R. Gomes1, Laura Woodley1, Karen Page2, David Guttery2, Lindsay Primrose2, Daniel Fernandez Garcia2, Jacqui Shaw2, Patrizia Viola3, Andrew Green4, Christopher Nolan4, Ian O. Ellis4, Emad A. Rakha4, Sami Shousha1, Eric W.-F. Lam1, Balázs Győrffy5, Mathieu Lupien6,7, R. Charles Coombes1
1Department of Surgery and Cancer, Imperial College London, London, UK
2Department of Cancer Studies, University of Leicester, Leicester, UK
3Laboratory of Medicine, Histopathology Department, Royal Brompton Hospital, London, UK
4Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Budapest, HU
5MTA TTK Lendület Cancer Biomarker Research Group; 2nd Department of Pediatrics, Semmelweis University and MTA-SE Pediatrics and Nephrology Research Group, Budapest, HU
6The Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
7Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Luca Magnani, e-mail: [email protected]
Keywords: breast cancer, estrogen receptor, drug resistance, metastasis, pioneer factors
Received: February 18, 2015 Accepted: June 02, 2015 Published: June 15, 2015
Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERα-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERα-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERα-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERα-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERα-positive breast cancer.
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