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      Obesity-associated NLRC4 inflammasome activation drives breast cancer progression

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          Abstract

          Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.

          Abstract

          Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.

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          Most cited references34

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          Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1.

          Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1alpha, IL-1beta, and IL-18. IL-1beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.
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            Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme.

            The interleukin-1 beta (IL-1 beta) converting enzyme (ICE) processes the inactive IL-1 beta precursor to the proinflammatory cytokine. Adherent monocytes from mice harboring a disrupted ICE gene (ICE-/-) did not export IL-1 beta or interleukin-1 alpha (IL-1 alpha) after stimulation with lipopolysaccharide. Export of tumor necrosis factor-alpha and interleukin-6 (IL-6) from these cells was also diminished. Thymocytes from ICE-/- mice were sensitive to apoptosis induced by dexamethasone or ionizing radiation, but were resistant to apoptosis induced by Fas antibody. Despite this defect in apoptosis, ICE-/- mice proceed normally through development.
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              Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer

              Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                06 October 2016
                2016
                : 7
                : 13007
                Affiliations
                [1 ]Department of Pathology, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [2 ]Center for Immunology and Immune Based Diseases, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [3 ]University of Texas Graduate School of Biomedical Sciences at Houston , Houston, Texas 77030, USA
                [4 ]Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center , Houston, Texas 77030, USA
                [5 ]Medical Scientist Training Program, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [6 ]Department of Nephrology, The Second Xiangya Hospital, Research Institute of Nephrology, Central South University , Changsha, Hunan 410011, China
                [7 ]Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [8 ]Department of Pharmacology, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [9 ]Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [10 ]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, Texas 77054, USA
                [11 ]Department of Pathology, University of California, San Diego , La Jolla, California 92093, USA
                [12 ]Cancer Biology Graduate Program, University of Texas MD Anderson Cancer Center , Houston, Texas 77030, USA
                [13 ]Department of Emergency Medicine, University of Texas MD Anderson Cancer Center , Houston, Texas 77030, USA
                [14 ]Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas 77030, USA
                [15 ]Department of Internal Medicine, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [16 ]Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                [17 ]Cancer Genes and Pathway Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine , Iowa City, Iowa 52242, USA
                Author notes
                [*]

                Present address: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

                Author information
                http://orcid.org/0000-0003-1194-216X
                Article
                ncomms13007
                10.1038/ncomms13007
                5059727
                27708283
                0775f5c9-faeb-465e-82cc-3fffba72647d
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 29 January 2016
                : 23 August 2016
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