title: ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.
abstract: During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Ledger
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Roden
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Andrew M K
authors.initials: AM
authors.lastname: Law
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Astrid
authors.initials: A
authors.lastname: Magenau
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kikhtyak
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Cho
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Allerdice
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Fatima
authors.initials: F
authors.lastname: Valdes-Mora
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Herrmann
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Salomon
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Adelaide I J
authors.initials: AI
authors.lastname: Young
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Lee
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Sergio
authors.affiliation: Peter Wills Bioinformatic Center, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Piggin
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: James R W
authors.initials: JR
authors.lastname: Conway
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|Department of Anatomical Pathology SEALS, St. George Hospital, Kogarah, New South Wales, Australia.|School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, New South Wales, Australia.
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chtanova
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Swarbrick
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Naylor
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Toole
authors.affiliation: Department of Histopathology, Nottingham City Hospital and Nottingham University, Nottingham, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.affiliation: Department of Histopathology, Nottingham City Hospital and Nottingham University, Nottingham, United Kingdom.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
authors.affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.|St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D002199:Capillary Permeability; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008212:Lymphocyte Depletion; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control; D020556:Neutrophil Infiltration; D011120:Polyomavirus / Q000472:pathogenicity; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors; D047368:Tumor Burden
chemical_list: D004268:DNA-Binding Proteins; C116038:ELF5 protein, human; D009363:Neoplasm Proteins; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins