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The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer

Magnani, Luca; Patten, Darren K.; Nguyen, Van T. M.; Hong, Sung-Pil; Steel, Jennifer H.; Patel, Naina; Lombardo, Ylenia; Faronato, Monica; Gomes, Ana R.; Woodley, Laura; Page, Karen; Guttery, David; Primrose, Lindsay; Garcia, Daniel Fernandez; Shaw, Jacqui; Viola, Patrizia; Green, Andrew; Nolan, Christopher; Ellis, Ian O.; Rakha, Emad A.; Shousha, Sami; Lam, Eric W.-F.; Gy?rffy, Bal�zs; Lupien, Mathieu; Coombes, Charles R.

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Authors

Luca Magnani

Darren K. Patten

Van T. M. Nguyen

Sung-Pil Hong

Jennifer H. Steel

Naina Patel

Ylenia Lombardo

Monica Faronato

Ana R. Gomes

Laura Woodley

Karen Page

David Guttery

Lindsay Primrose

Daniel Fernandez Garcia

Jacqui Shaw

Patrizia Viola

Christopher Nolan

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Sami Shousha

Eric W.-F. Lam

Bal�zs Gy?rffy

Mathieu Lupien

Charles R. Coombes



Abstract

Over 30% of ER? 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 ER? binding. Here we demonstrate that PBX1 plays a central role in regulating the ER? transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ER? 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 ER?-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ER?-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 ER?-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 ER?-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ER?-positive breast cancer.

Citation

Magnani, L., Patten, D. K., Nguyen, V. T. M., Hong, S., Steel, J. H., Patel, N., …Coombes, C. R. (2015). The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer. Oncotarget, 6(26), 21878-21891. https://doi.org/10.18632/oncotarget.4243

Journal Article Type Article
Acceptance Date Jun 2, 2015
Online Publication Date Jun 16, 2015
Publication Date Sep 8, 2015
Deposit Date Oct 16, 2018
Publicly Available Date Oct 18, 2018
Journal Oncotarget
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 6
Issue 26
Pages 21878-21891
DOI https://doi.org/10.18632/oncotarget.4243
Public URL https://nottingham-repository.worktribe.com/output/1170273
Publisher URL http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=4243&path[]=11612