title: Effects of the MCP-1 synthesis inhibitor bindarit on tumorigenesis and inflammatory markers in the C3(1)/SV40Tag mouse model of breast cancer.
abstract: Breast cancer, the most deadly cancer in women, is characterized by elevated levels of inflammation within and surrounding the tumor, which can lead to accelerated growth, invasion and metastasis. Macrophages are central to the inflammatory milieu and are recruited to the tumor microenvironment by several factors including monocyte chemoattractant protein-1 (MCP-1). Using the anti-inflammatory molecule bindarit to target MCP-1, we investigated the role of this chemokine on macrophage related inflammation and mammary tumorigenesis in a transgenic mouse model of breast cancer. C3(1)/SV40Tag mice and wild type FVB/N were randomized to either control or 0.5% bindarit diet from 4 to 21weeks of age. Tumor number and volume were recorded over time and at sacrifice. Macrophage markers as well as inflammatory meditators were examined in the tumor tissue and mammary glands. Circulating MCP-1 and IL-6 were measured by ELISA. Bindarit treatment reduced tumor number (P<0.05), but did not affect tumor size, tumor weight or tumor latency in C3(1)/SV40Tag mice. Within the tumor, mRNA expression of bindarit's primary targets, MCP-1 and IL-12/p35, were significantly decreased by bindarit treatment (P<0.05), and this was consistent with trends for reduced expression of TNF-α, IL-6, F4/80, CD206, and IL-10. In mammary tissue, expression of MCP-1, TNF-α, IL-6, F4/80, IL-10 and IL-12/p35 was significantly elevated in C3(1)/SV40Tag mice compared to wild type FVB/N mice, but IL-6 was the only marker decreased by bindarit treatment (P<0.05). Plasma MCP-1 was highly correlated with tumor volume (P<0.05); however, it was not affected by bindarit at 21weeks of age. Similarly, circulating IL-6 was increased in C3(1)/SV40Tag mice but there was no effect of bindarit treatment. These results show that tumor multiplicity in the C3(1)/SV40Tag mouse model of breast cancer is reduced by bindarit, however these effects are independent of changes in plasma levels of MCP-1 and IL-6, but may be related to the attenuated expression of MCP-1 along with several inflammatory mediators and macrophage markers within the tumor.
authors.affiliation: Department of Pathology Microbiology and Immunology, School of Medicine at South Carolina, Columbia, SC 29209, United States; Department of Exercise Science, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: J L
authors.initials: JL
authors.lastname: Steiner
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: J M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Department of Pathology Microbiology and Immunology, School of Medicine at South Carolina, Columbia, SC 29209, United States; Department of Exercise Science, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: J L
authors.initials: JL
authors.lastname: McClellan
authors.affiliation: Angelini, ACRAF, S. Palomba-Pomezia, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Guglielmotti
authors.affiliation: Department of Pathology Microbiology and Immunology, School of Medicine at South Carolina, Columbia, SC 29209, United States. Electronic address: Angela.Murphy@uscmed.sc.edu.
authors.forename: E A
authors.initials: EA
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D015415:Biomarkers; D018932:Chemokine CCL2; D007191:Indazoles; D018836:Inflammation Mediators; D015850:Interleukin-6; D011422:Propionates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C079489:bindarit
keywords: Bindarit; C3(1)/SV40Tag transgenic mice; MCP-1; Mammary cancer