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

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, Andrew Green, Christopher Nolan, Ian O. Ellis, Emad A. RakhaSami Shousha, Eric W.F. Lam, Balázs Gyorffy, Mathieu Lupien, R. Charles Coombes

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21878-21891
Number of pages14
JournalOncotarget
Volume6
Issue number26
DOIs
Publication statusPublished - Jan 1 2015

Keywords

  • Breast cancer
  • Drug resistance
  • Estrogen receptor
  • Metastasis
  • Pioneer factors

ASJC Scopus subject areas

  • Oncology

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    Magnani, L., Patten, D. K., Nguyen, V. T. M., Hong, S. P., Steel, J. H., Patel, N., Lombardo, Y., Faronato, M., Gomes, A. R., Woodley, L., Page, K., Guttery, D., Primrose, L., Garcia, D. F., Shaw, J., Viola, P., Green, A., Nolan, C., Ellis, I. O., ... Coombes, R. C. (2015). The pioneer factor PBX1 is a novel driver of metastatic progression in ER'-positive breast cancer. Oncotarget, 6(26), 21878-21891. https://doi.org/10.18632/oncotarget.4243