title: Obesity-associated NLRC4 inflammasome activation drives breast cancer progression.
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.
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Center for Immunology and Immune Based Diseases, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kolb
authors.affiliation: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Liem
authors.identifier: 0000-0003-1194-216X
authors.initials: L
authors.lastname: Phan
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Borcherding
authors.affiliation: Department of Nephrology, The Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan 410011, China.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nephrology, The Second Xiangya Hospital, Research Institute of Nephrology, Central South University, Changsha, Hunan 410011, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Janowski
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Markan
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Fuentes-Mattei
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
authors.affiliation: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Cancer Biology Graduate Program, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
authors.affiliation: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Sai-Ching J
authors.initials: SJ
authors.lastname: Yeung
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cassel
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.|Cancer Genes and Pathway Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D009368:Neoplasm Transplantation; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C435692:NLRC4 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse