52 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1091-1096
Number of pages6
JournalOncology reports
Volume14
Issue number4
StatePublished - Oct 1 2005

Fingerprint

Catechol Estrogens
Estrogens
Breast
Breast Neoplasms
Catechol O-Methyltransferase
Enzymes
NADP
Quinones
Aromatase
Oxidoreductases
DNA
Mammaplasty
Mastectomy
Methylation
Androgens
Glutathione
Real-Time Polymerase Chain Reaction
RNA
Gene Expression
Messenger RNA

Keywords

  • COMT
  • CYP19
  • CYP1B1
  • Estrogen metabolism
  • Human breast
  • NQO1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. / Singh, Seema; Chakravarti, Dhrubajyoti; Edney, James A.; Hollins, Ronald Ray; Johnson, Perry James; West, William W.; Higginbotham, Sheila M.; Cavalieri, Ercole; Rogan, Eleanor G.

In: Oncology reports, Vol. 14, No. 4, 01.10.2005, p. 1091-1096.

Research output: Contribution to journalArticle

Singh, Seema ; Chakravarti, Dhrubajyoti ; Edney, James A. ; Hollins, Ronald Ray ; Johnson, Perry James ; West, William W. ; Higginbotham, Sheila M. ; Cavalieri, Ercole ; Rogan, Eleanor G. / Relative imbalances in the expression of estrogen-metabolizing enzymes in the breast tissue of women with breast carcinoma. In: Oncology reports. 2005 ; Vol. 14, No. 4. pp. 1091-1096.
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abstract = "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.",
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author = "Seema Singh and Dhrubajyoti Chakravarti and Edney, {James A.} and Hollins, {Ronald Ray} and Johnson, {Perry James} and West, {William W.} and Higginbotham, {Sheila M.} and Ercole Cavalieri and Rogan, {Eleanor G}",
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AU - Singh, Seema

AU - Chakravarti, Dhrubajyoti

AU - Edney, James A.

AU - Hollins, Ronald Ray

AU - Johnson, Perry James

AU - West, William W.

AU - Higginbotham, Sheila M.

AU - Cavalieri, Ercole

AU - Rogan, Eleanor G

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