Cyclooxygenase-2 and the inflammogenesis of breast cancer

Figure 5 Model of COX-2-driven inflammogenesis of breast cancer. Key steps in the transition of normal mammary ductal epithelium to invasive cancer are as follows: (1) Healthy mammary adipose maintains homeostasis of the mammary epithelium; (2) Pro-inflammatory stimuli (e.g., adipokines, cytokines and n-6 PUFA) induce macrophage infiltration and chronic inflammation of the mammary stroma; (3) COX-2 is upregulated and constitutively expressed by adipocytes, immune cells and epithelial cells; (4) COX-2-catalyzed PGE-2 induces transcription of the CYP-19 gene and aromatase-catalyzed estrogen biosynthesis by adipocytes; (5) Estrogen stimulates estrogen receptors of epithelial cells to promote cell proliferation; (6) PGE-2 induces CYP-1B1 in epithelial cells resulting in hydroxylation of estrogen that is converted to estrogen quinone that has mutagenic impact; and (7) PGE-2 induces a profile of genes in epithelial cells that promote angiogenesis, loss of apoptosis, immunosuppression and metastasis (see text for discussion). COX-2: Cyclooxygenase-2; PGE-2: Prostaglandin E2; n-6 PUFA: n-6 polyunsaturated fatty acids.