Promoter switching of CYP19

Carcinogenesis (MDAfrom PGH2)

Figure 2. COX-2 and mechanisms of carcinogenesis.

Furthermore, increased prostaglandin levels lead to a rise in cellular cyclic AMP (cAMP). This can directly result in reduced apoptosis and increased cell survival. The aromatase gene CYP19, is responsible for local oestrogen biosynthesis in breast cancer, and therefore, is an important influence in the development and growth of hormone-dependent tumours (74).

Prostaglandin E2 (PGE2) facilitates switching of expression of CYP19 from promoter 1.4 to promoter II in adipose stromal cells, thereby leading to a three- to four-fold increase in activity (75, 76). In support of linkage between the two enzyme systems, there is a significant correlation between COX-2 and CYP19 mRNA levels in breast cancer (75).

PGE2 may itself induce COX-2 expression by binding to the PGE receptor. Cell line work has shown incubation of a mouse osteoblastic cell line with TNF-alpha leads to a biphasic increase in COX-2 production. The second phase of COX-2 expression is considered to be the result of induction by accumulated PGE2 (77).

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