title: The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.
abstract: 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.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Darren K
authors.initials: DK
authors.lastname: Patten
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Van T M
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sung-Pil
authors.initials: SP
authors.lastname: Hong
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Naina
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Faronato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Woodley
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Page
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: David
authors.initials: D
authors.lastname: Guttery
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Primrose
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernandez Garcia
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Laboratory of Medicine, Histopathology Department, Royal Brompton Hospital, London, UK.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Viola
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Budapest, HU.
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Budapest, HU.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nolan
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Budapest, HU.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Budapest, HU.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sami
authors.initials: S
authors.lastname: Shousha
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, 2nd Department of Pediatrics, Semmelweis University and MTA-SE Pediatrics and Nephrology Research Group, Budapest, HU.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: The Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human
keywords: breast cancer; drug resistance; estrogen receptor; metastasis; pioneer factors