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ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells

Gallego-Ortega, David, Ledger, Anita, Roden, Daniel L., Law, Andrew M. K., Magenau, Astrid, Kikhtyak, Zoya, Cho, Christina, Allerdice, Stephanie L., Lee, Heather J., Valdes-Mora, Fatima, Herrmann, David, Salomon, Robert, Young, Adelaide I. J., Lee, Brian Y., Sergio, C. Marcelo, Kaplan, Warren, Piggin, Catherine, Conway, James R. W., Rabinovich, Brian, Millar, Ewan K. A., Oakes, Samantha R., Chtanova, Tatyana, Swarbrick, Alexander, Naylor, Matthew J., O'Toole, Sandra, Green, Andrew R., Timpson, Paul, Gee, Julia M.W., Ellis, Ian O., Clark, Susan J. and Ormandy, Christopher J. 2015. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biology 13 (12) , e1002330. 10.1371/journal.pbio.1002330

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Additional Information: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Publisher: Public Library of Science
ISSN: 1545-7885
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 17 November 2015
Last Modified: 14 Sep 2020 10:15

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