Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma.
Estrogens are a known risk factor for breast cancer. Studies indicate that initiation of breast cancer may occur by metabolism of estrogens to form abnormally high levels of catechol estrogen-3,4-quinones, which can then react with DNA to form depurinating adducts and, subsequently, induce mutations that lead to cancer. Among the key enzymes metabolizing estrogens are two activating enzymes: cytochrome P450 (CYP)19 (aromatase), which converts androgens to estrogens, and CYP1B1, which converts estrogens predominantly to the 4-catechol estrogens that are further oxidized to catechol estrogen-3,4-quinones. Formation of the quinones is prevented by methylation of the 4-catechol estrogens by the enzyme, catechol-O-methyltransferase (COMT). In addition, catechol estrogen quinones can be reduced back to catechol estrogens by NADPH quinone oxidoreductase 1 (NQO1) and/or are coupled with glutathione, preventing reaction with DNA. Thus, COMT and NQO1 are key deactivating enzymes. In this initial study, we examined whether the expression of these four critical estrogen activating/deactivating enzymes is altered in breast cancer. Control breast tissue was obtained from four women who underwent reduction mammoplasty. Breast tissues from five women with breast carcinoma, who underwent mastectomy, were used as cases. The level of expression of CYP19, CYP1B1, COMT and NQO1 mRNAs was quantified from total RNA using a real time RT-PCR method in an ABI PRISM 7700 sequence detection system. The control breast tissues showed lower expression of the activating enzymes, CYP19 and CYP1B1, and higher expression of the deactivating enzymes, COMT and NQO1, compared to the cases. In the cases, the reverse pattern was observed: greater expression of activating enzymes and lower expression of deactivating enzymes. Thus, in women with breast cancer, estrogen metabolism may be related to altered expression of multiple genes. These unbalances appear to be instrumental in causing excessive formation of catechol estrogen quinones that, by reacting with DNA, initiate the series of events leading to breast cancer.
Singh
Seema
S
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Chakravarti
Dhrubajyoti
D
Edney
James A
JA
Hollins
Ronald R
RR
Johnson
Perry J
PJ
West
William W
WW
Higginbotham
Sheila M
SM
Cavalieri
Ercole L
EL
Rogan
Eleanor G
EG
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D001141:Aromatase / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D008956:Models, Chemical; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013997:Time Factors
D004967:Estrogens; D012333:RNA, Messenger; D012313:RNA; D004247:DNA; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D002394:Catechol O-Methyltransferase; D010100:Oxygen