The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.pdf (1.98 MB)
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The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.

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journal contribution
posted on 16.11.2017, 09:58 by L Magnani, DK Patten, VTM Nguyen, S-P Hong, JH Steel, N Patel, Y Lombardo, M Faronato, AR Gomes, L Woodley, Karen Page, David Guttery, Lindsay Primrose, D Fernandez Garcia, Jacqui Shaw, P Viola, A Green, C Nolan, IO Ellis, EA Rakha, S Shousha, EW-F Lam, B Győrffy, M Lupien, RC Coombes
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.

History

Citation

Oncotarget, 2015, 6 (26), pp. 21878-21891

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

VoR (Version of Record)

Published in

Oncotarget

Publisher

Impact Journals

eissn

1949-2553

Acceptance date

02/06/2015

Copyright date

2015

Available date

16/11/2017

Publisher version

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=4243&path[]=11612

Language

en