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PLoS Biol. 2015 Dec 30;13(12):e1002330. doi: 10.1371/journal.pbio.1002330. eCollection 2015 Dec.

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

Author information

1
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
2
St. Vincent's Clinical School of Medicine, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales, Australia.
3
Peter Wills Bioinformatic Center, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
4
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
5
Department of Anatomical Pathology SEALS, St. George Hospital, Kogarah, New South Wales, Australia.
6
School of Medicine and Health Sciences, University of Western Sydney, Campbelltown, New South Wales, Australia.
7
Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
8
Department of Histopathology, Nottingham City Hospital and Nottingham University, Nottingham, United Kingdom.
9
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.

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.

PMID:
26717410
PMCID:
PMC4696735
DOI:
10.1371/journal.pbio.1002330
[Indexed for MEDLINE]
Free PMC Article

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