Abstract
IntroductionOverexpression of cyclooxygenase (COX-2) is commonly observed in human cancers. In a murine model of metastatic breast cancer, we observed that COX-2 expression and enzyme activity were associated with enhanced tumorigenic and metastatic potential. In contrast to the high COX-2 expression in metastatic tumors, transplantation of poorly tumorigenic tumor cell lines to syngeneic mice results in less COX-2 expression and less COX-2 activity in vivo. Aberrant CpG island methylation, and subsequent silencing of the COX-2 promoter, has been observed in human cancer cell lines and in some human tumors of the gastrointestinal tract.MethodsUsing bisulfite modification and a methylation-specific PCR, we examined the methylation status of the COX-2 promoter in a series of four closely-related murine mammary tumors differing in COX-2 expression and metastatic potential.ResultsWe showed that line 410, which does not express COX-2 in vivo, exhibited evidence of promoter methylation. Interestingly, the metastatic counterpart of this cell (line 410.4) displayed only the unmethylated COX-2 promoter, as did two additional cell lines (lines 66.1 and 67). The methylation patterns observed in vitro were maintained when these murine mammary tumor lines were transplanted to syngeneic mice. Treatment with the DNA demethylating agent 5-aza-deoxycytidine increased COX-2 mRNA, increased protein and increased enzyme activity (prostaglandin synthesis).ConclusionsThese results indicate that COX-2 promoter methylation may be one mechanism by which tumor cells regulate COX-2 expression. Upregulation of COX-2 expression in closely related metastatic lesions versus nonmetastatic lesions may represent a shift towards the unmethylated phenotype.
Highlights
Overexpression of cyclooxygenase (COX-2) is commonly observed in human cancers
We showed that line 410, which does not express COX-2 in vivo, exhibited evidence of promoter methylation
Treatment with the DNA demethylating agent 5-aza-deoxycytidine increased COX-2 mRNA, increased protein and increased enzyme activity. These results indicate that COX-2 promoter methylation may be one mechanism by which tumor cells regulate COX-2 expression
Summary
In a murine model of metastatic breast cancer, we observed that COX-2 expression and enzyme activity were associated with enhanced tumorigenic and metastatic potential. Reports in breast cancer suggested a linkage between prostaglandin production and aggressive disease [9,10], but less is known regarding the specific contribution of the COX-2 isoform to behavior. Studies are beginning to emerge that suggest heightened COX-2 expression is associated with more aggressive breast cancer [11,12,13]. We have examined COX-2 expression in a murine model of metastatic breast cancer and have observed that COX-2 protein expression in vivo, as well as COX-2 enzyme activity (i.e. prostaglandin E2 [PGE2] synthesis), is positively correlated with more aggressive disease [14]. Selective COX-2 or COX-1 inhibitors control metastatic disease in this model system [15]
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