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

Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, Cho C, Allerdice SL, Lee HJ, Valdes-Mora F, Herrmann D, Salomon R, Young AI, Lee BY, Sergio CM, Kaplan W, Piggin C, Conway JR, Rabinovich B, Millar EK, Oakes SR, Chtanova T, Swarbrick A, Naylor MJ, O'Toole S, Green AR, Timpson P, Gee JM, Ellis IO, Clark SJ, Ormandy CJ - PLoS Biol. (2015)

Bottom Line: 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.Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.

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.

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Effect of depletion of MDSC on ELF5-driven lung metastasis and vascular permeability.Panel A, representative plot of the depletion of Ly6G+ cells by treatment for 2 wk with the Ly6G antibody. Panel B, Time course for the depletion of neutrophils by treatment with the Ly6G antibody. Panel C, Effects of Ly6G antibody treatment on tumor infiltrated MDSC in mice of the indicated genotypes. Panel D, effect of Ly6G treatment on total ROS production in the CD11b+ myeloid population measured by FACS. Panel E, effect of Ly6G treatment on lung metastases. Panel F, effects of treatment with the Ly6G antibody on tumor vasculature leakiness. RBC: red blood cells. Raw data for panels B and C can be found at S4 Data.
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pbio.1002330.g007: Effect of depletion of MDSC on ELF5-driven lung metastasis and vascular permeability.Panel A, representative plot of the depletion of Ly6G+ cells by treatment for 2 wk with the Ly6G antibody. Panel B, Time course for the depletion of neutrophils by treatment with the Ly6G antibody. Panel C, Effects of Ly6G antibody treatment on tumor infiltrated MDSC in mice of the indicated genotypes. Panel D, effect of Ly6G treatment on total ROS production in the CD11b+ myeloid population measured by FACS. Panel E, effect of Ly6G treatment on lung metastases. Panel F, effects of treatment with the Ly6G antibody on tumor vasculature leakiness. RBC: red blood cells. Raw data for panels B and C can be found at S4 Data.

Mentions: To determine if the increase in MDSC could account for the increase in metastases caused by ELF5, we used the specific Ly6G antibody to deplete the granulocytic MDSC population during induction of ELF5 in PyMT tumors. Two weeks of treatment with the rat Ly6G antibody resulted in a consistent and efficient depletion, no granulocytic MDSCs were observed in the blood of Ly6G-treated animals (Fig 7A), and a 98% depletion of tumor-infiltrated MDSC was observed (Fig 7B). As a result, only 1.5% of infiltrated Ly6G+ granulocytic MDSC cells were identified in both PyMT/WT and PyMT/ELF5 tumors in the CD11b+ compartment (Fig 7C). Ly6G depletion did not significantly affect the numbers of other infiltrated immune populations in PyMT tumors (S6 Fig). An analysis of the ROS production in the tumor infiltrated CD11b+ myeloid population showed a reduction of total ROS producing cells, consistent with a Ly6G granulocytic cell depletion and a less immune-permissive environment (Fig 7D). MDSC depletion reduced the number of lung metastases in both WT and ELF5 tumors (Fig 7E). We also observed that the antibody treatment reduced the number of red blood cells within the primary tumor (Fig 7F), establishing MDSCs as a key part of the mechanism responsible for both induction of metastases and the hemorrhagic tumor phenotype by ELF5.


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

Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, Cho C, Allerdice SL, Lee HJ, Valdes-Mora F, Herrmann D, Salomon R, Young AI, Lee BY, Sergio CM, Kaplan W, Piggin C, Conway JR, Rabinovich B, Millar EK, Oakes SR, Chtanova T, Swarbrick A, Naylor MJ, O'Toole S, Green AR, Timpson P, Gee JM, Ellis IO, Clark SJ, Ormandy CJ - PLoS Biol. (2015)

Effect of depletion of MDSC on ELF5-driven lung metastasis and vascular permeability.Panel A, representative plot of the depletion of Ly6G+ cells by treatment for 2 wk with the Ly6G antibody. Panel B, Time course for the depletion of neutrophils by treatment with the Ly6G antibody. Panel C, Effects of Ly6G antibody treatment on tumor infiltrated MDSC in mice of the indicated genotypes. Panel D, effect of Ly6G treatment on total ROS production in the CD11b+ myeloid population measured by FACS. Panel E, effect of Ly6G treatment on lung metastases. Panel F, effects of treatment with the Ly6G antibody on tumor vasculature leakiness. RBC: red blood cells. Raw data for panels B and C can be found at S4 Data.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4696735&req=5

pbio.1002330.g007: Effect of depletion of MDSC on ELF5-driven lung metastasis and vascular permeability.Panel A, representative plot of the depletion of Ly6G+ cells by treatment for 2 wk with the Ly6G antibody. Panel B, Time course for the depletion of neutrophils by treatment with the Ly6G antibody. Panel C, Effects of Ly6G antibody treatment on tumor infiltrated MDSC in mice of the indicated genotypes. Panel D, effect of Ly6G treatment on total ROS production in the CD11b+ myeloid population measured by FACS. Panel E, effect of Ly6G treatment on lung metastases. Panel F, effects of treatment with the Ly6G antibody on tumor vasculature leakiness. RBC: red blood cells. Raw data for panels B and C can be found at S4 Data.
Mentions: To determine if the increase in MDSC could account for the increase in metastases caused by ELF5, we used the specific Ly6G antibody to deplete the granulocytic MDSC population during induction of ELF5 in PyMT tumors. Two weeks of treatment with the rat Ly6G antibody resulted in a consistent and efficient depletion, no granulocytic MDSCs were observed in the blood of Ly6G-treated animals (Fig 7A), and a 98% depletion of tumor-infiltrated MDSC was observed (Fig 7B). As a result, only 1.5% of infiltrated Ly6G+ granulocytic MDSC cells were identified in both PyMT/WT and PyMT/ELF5 tumors in the CD11b+ compartment (Fig 7C). Ly6G depletion did not significantly affect the numbers of other infiltrated immune populations in PyMT tumors (S6 Fig). An analysis of the ROS production in the tumor infiltrated CD11b+ myeloid population showed a reduction of total ROS producing cells, consistent with a Ly6G granulocytic cell depletion and a less immune-permissive environment (Fig 7D). MDSC depletion reduced the number of lung metastases in both WT and ELF5 tumors (Fig 7E). We also observed that the antibody treatment reduced the number of red blood cells within the primary tumor (Fig 7F), establishing MDSCs as a key part of the mechanism responsible for both induction of metastases and the hemorrhagic tumor phenotype by ELF5.

Bottom Line: 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.Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.

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.

Show MeSH
Related in: MedlinePlus