Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinogenesis.
The present study was performed to investigate the critical role of 5-lipoxygenase (5-LOX) in 7,12-dimethylbenz(α)anthracene (DMBA)-induced rat mammary inflammation associated carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(α)anthracene (DMBA; 0.5 mg/100 g body weight) by a single tail vein injection, followed by administration of zileuton (2000 mg/kg diet) from week 7 until the termination of the study at 31 wk. 5-LOX protein expression, 5-hydroxyeicosatetraenoic acid (5-HETE), and leukotriene B4 (LTB4 ) production in rat mammary tissue were analyzed at 6, 12, and 24 wk post-DMBA injection. Rate of cell proliferation was analyzed by bromodioxyuridine labeling index (BrdU-LI). Microvessel density, level of VEGF, and MMP-2 were also measured. DMBA induces inflammation in rat mammary gland as early as 6 wk. 5-LOX is upregulated in DMBA treated rats right from 6 wk when compared with their normal counterparts. An overexpression of 5-LOX is accompanied with increase in 5-HETE, LTB4 production and high BrdU-LI with an increase of two key angiogenic factors for tumorigenesis; MMP-2 and VEGF. It was found that 5-LOX specific inhibitor brought about substantial protection against DMBA-induced mammary carcinogenesis. Histological findings showed substantial repair of hyperplastic lesions. There was a significant reduction in the rate of cell proliferation and expression of angiogenic factors, MMP-2 and VEGF. 5-LOX plays an important role in DMBA-induced inflammation associated carcinogenesis via activation of MMP-2 and VEGF. 5-LOX expression can be considered as a critical event in controlling the process of mammary tumor development.
Chemical Carcinogenesis and Chemoprevention Laboratory, Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India.
Mary
M
Chatterjee
Subhadeep
S
Das
Kaushik
K
Roy
Malay
M
Chatterjee
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D006893:Hydroxyeicosatetraenoic Acids; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D001094:Arachidonate 5-Lipoxygenase; D020778:Matrix Metalloproteinase 2