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

David Gallego-Ortega; Anita Ledger; Daniel L Roden; Andrew M K Law; Astrid Magenau; Zoya Kikhtyak; Christina Cho; Stephanie L Allerdice; Heather J Lee; Fatima Valdes-Mora; David Herrmann; Robert Salomon; Adelaide I J Young; Brian Y Lee; C Marcelo Sergio; Warren Kaplan; Catherine Piggin; James R W Conway; Brian Rabinovich; Ewan K A Millar; Samantha R Oakes; Tatyana Chtanova; Alexander Swarbrick; Matthew J Naylor; Sandra O'Toole; Andrew R Green; Paul Timpson; Julia M W Gee; Ian O Ellis; Susan J Clark; Christopher J Ormandy

doi:10.1371/journal.pbio.1002330

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

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

Authors

David Gallego-Ortega^{1

2}, Anita Ledger¹, Daniel L Roden^{1

2}, Andrew M K Law¹, Astrid Magenau^{1

2}, Zoya Kikhtyak¹, Christina Cho¹, Stephanie L Allerdice¹, Heather J Lee¹, Fatima Valdes-Mora^{1

2}, David Herrmann^{1

2}, Robert Salomon¹, Adelaide I J Young¹, Brian Y Lee¹, C Marcelo Sergio¹, Warren Kaplan³, Catherine Piggin¹, James R W Conway¹, Brian Rabinovich⁴, Ewan K A Millar^{1

5

6}, Samantha R Oakes^{1

2}, Tatyana Chtanova¹, Alexander Swarbrick^{1

2}, Matthew J Naylor^{1

7}, Sandra O'Toole^{1

7}, Andrew R Green⁸, Paul Timpson^{1

2}, Julia M W Gee⁹, Ian O Ellis⁸, Susan J Clark^{1

2}, Christopher J Ormandy^{1

2}

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / immunology
Breast Neoplasms / metabolism*
Breast Neoplasms / physiopathology
Breast Neoplasms / virology
Capillary Permeability
Cell Proliferation
DNA-Binding Proteins
Female
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Hemorrhage / etiology
Hemorrhage / prevention & control
Humans
Leukocytes / immunology
Leukocytes / pathology
Lung / blood supply
Lung / immunology
Lung / metabolism*
Lung / pathology
Lung Neoplasms / blood supply
Lung Neoplasms / pathology
Lung Neoplasms / prevention & control
Lung Neoplasms / secondary*
Lymphocyte Depletion
Mice, Transgenic
Myeloid Cells / immunology
Myeloid Cells / pathology
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neovascularization, Pathologic / etiology
Neovascularization, Pathologic / prevention & control
Neutrophil Infiltration
Polyomavirus / pathogenicity
Proto-Oncogene Proteins c-ets / genetics
Proto-Oncogene Proteins c-ets / metabolism*
Recombinant Fusion Proteins / metabolism
Survival Analysis
Transcription Factors
Tumor Burden

Substances

DNA-Binding Proteins
ELF5 protein, human
Neoplasm Proteins
Proto-Oncogene Proteins c-ets
Recombinant Fusion Proteins
Transcription Factors
enhanced green fluorescent protein
Green Fluorescent Proteins

Grants and funding

This work has been supported by the National Health and Medical Research Council (NHMRC) Australia (Project grant and Fellowship to CJO), Cancer Council New South Wales (NSW), National Breast Cancer Foundation Australia, Cancer Institute NSW, Banque Nationale de Paris Paribas Australia. DGO and FVM are Fellows of the National Breast Cancer Foundation and Cure Cancer Foundation Australia. SRO is a National Breast Cancer Foundation Fellow JMWG is a Breast Cancer Now Fellow. URLs: National Health and Medical Research Council: http://www.nhmrc.gov.au/; National Breast Cancer Foundation Australia: http://www.nbcf.org.au/; Cancer Council New South Wales (NSW): http://www.cancercouncil.com.au/; Cancer Institute NSW: https://www.cancerinstitute.org.au/; Banque Nationale de Paris Paribas Australia: http://www.bnpparibas.com.au/en/; Breast Cancer Now: http://breastcancernow.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.