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.
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