title: Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation.
abstract: Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China,. Electronic address: liuqy@immunol.org.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, and.
authors.forename: Qinchun
authors.initials: Q
authors.lastname: Tan
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, and.
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, and.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China,; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, and; National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address: caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000912:Antibodies, Neoplasm; C491901:FAS protein, human; C491899:Fas protein, mouse; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019014:fas Receptor; D015232:Dinoprostone
keywords: Breast Cancer; Fas; IL-6; Inflammation; MDSC; PGE2; Prostaglandins; Tumor Metastases