A Potential Role for the Estrogen-metabolizing Cytochrome P450 Enzymes in Human Breast Carcinogenesis

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Abstract
Purpose. The cytochrome P450 (CYP) enzymes play a critical role in the oxidative metabolism of a variety of endogenous and exogenous compounds, including drugs. Although intermediate CYP metabolites are believed to play a role in carcinogenesis, little is known about tissue-specific CYP expression and the role of local activation in breast carcinogenesis. The goals of this study are to identify CYPs expressed in breast tissue by measuring mRNA levels and to determine whether there are differences in mRNA levels between breast tumors and histologically-normal adjacent breast tissue. Experimental design. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was used to quantitate mRNA expression levels of 11 CYPs in 29 human breast tumor and non-tumor adjacent tissue pairs. The CYPs examined included: CYP1A1, CYP1A2, CYP1B1, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Results. Only four CYPs were detected in breast tumor or adjacent tissue: CYP1A1, CYP1B1, CYP2C9, CYP3A4. Each of these CYPs was expressed in at least 75% of the samples. Three of these CYPs are involved in estradiol hydroxylation (CYP1A1, 2-OH; CYP1B1, 4-OH; CYP3A4, 2- and 16-OH). CYP2C9 is involved in the conversion of estrone sulfate to the 16-hydroxy sulfate metabolite. Higher levels of CYP1B1 and 3A4 were found more often in non-tumor tissue than in tumor tissue (P < 0.04). CYP1A1 was elevated in non-tumor tissue only among pairs in which the tumor expressed the estrogen receptor (ER+, P < 0.03). All of these results were independent of recorded clinical–pathological covariates. Conclusions. CYPs involved in estrogen metabolism are expressed in both tumor and non-tumor breast tissue. Local activation of estrogen to potentially reactive metabolites by the CYPs in breast tissue may play a role in initiating and promoting the carcinogenic process.