© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 27, 15-16,
2000
© 2000 Oxford University Press
Symposium Overview
Correspondence to: Richard J. Santen, M.D., Division of Hematology, Oncology, and Endocrinology, P.O. Box 334, Cancer Center-Rm. 4023, University of Virginia Health Science Center, Charlottesville, VA 22908 (e-mail: rjs5y{at}virginia.edu).
 |
INTRODUCTION |
|---|
 TopNotes Introduction |
|---|
My role today is to preview the concepts that will be presented over the course of this meeting and to provide a framework for integration. Estradiol (E2) can potentially act to mediate carcinogenesis via two separate pathways. One pathway involves receptor-mediated stimulation of biologic events, and the other involves the metabolism of E2 to compounds, resulting in DNA damage and mutations. As Fig. 1
shows, E2 binds to its receptor and initiates transcription of genes involved in cellular proliferation. The frequency of genetic mutations parallels the increase in the number of cell divisions. In addition, the time available for DNA repair diminishes. This pathway is generally believed to be the one responsible for estrogen-induced carcinogenesis. Understanding of the physiology of receptor-mediated transcription has increased substantially during the last several years. A second estrogen receptor, the 
-receptor, has been described recently and studied intensively. Receptor variants occur; co-activators, corepressors, and integrator proteins modulate estrogen-induced transcription and responsiveness to both estrogens and antiestrogens. These form the subject of several of the talks that review this rapidly advancing field (see Chapter 8).
|
A second pathway (Fig. 2
) has been proposed as a mediator of estrogen-induced carcinogenesis. This pathway involves the metabolism of E2 to the catechol estrogen 4-hydroxyestradiol (4-OHE2) and then to a further oxidized metabolite, E2-3,4-quinone (see Chapters 4 and 5). This metabolite can bind to either guanine or adenine in DNA to form guanine–quinone or adenine–quinone adducts. (Only the guanine–quinone adducts are shown in Fig. 2.) Reaction of the quinone with guanine or adenine destabilizes the glycosidic bond, leading to the depurination of the DNA. When the depurinated DNA replicates, both G to T and A to T point mutations can occur.
|
The metabolism of 4-OHE2 is reversible through a quinone reductase enzyme. Of interest, this enzyme can be stimulated by tamoxifen. Oxido-reduction between catechol estrogens, semiquinones, and quinones generates reactive oxygen species that damage DNA extensively. Two major pathways are protective of this potentially harmful oxidative metabolic sequence. One involves the catechol-O-methyltransferase enzyme, which converts 4-OHE2 to 4-methoxyE2; the other neutralizes E2-3,4-quinone by conjugation with glutathione. Alterations of these detoxification steps could enhance or reduce the incidence of breast cancer, a topic to be discussed later (see Chapter 6).
Consideration of these two separate pathways does not imply that each may act exclusively of the other (Fig. 3). It is considered likely that these two mechanisms work in either an additive or a synergistic manner to mediate carcinogenesis. The mutations induced specifically by depurinating adducts and generally by oxidative DNA damage would be propagated by the genomic effects of E2 on cellular proliferation.
|
The plausibility that the metabolic pathway leading to DNA adducts is biologically significant has been questioned. The primary basis for this critique is that insufficient concentrations of E2 are present in tissue to allow accumulation of biologically meaningful amounts of critical metabolites. However, recent observations suggest that breast tissue can synthesize E2 in situ (see Chapter 5). Under these circumstances, much more E2 would be present in tissue than would be predicted from plasma concentrations. The rate-limiting step in estrogen biosynthesis is aromatase, a member of the cytochrome P450 class of enzymes (Fig. 4
). This enzyme converts androstenedione to estrone and testosterone to E2. Breast tissue contains 17-oxidoreductase, the enzyme that continuously interconverts estrone and E2. Overexpression of aromatase in the breast would substantially increase tissue E2 levels. Several animal models of aromatase overexpression and breast cancer have been described, which support the possibility of a role for this enzyme in carcinogenesis. Furthermore, overexpression of cytochrome P450 1B1, which converts E2 to 4-OHE2, could also result in accumulation of higher amounts of genotoxic E2 metabolites (see Chapter 5).
|
Several presentations will address issues of molecular epidemiology suggested by these pathways (see Chapters 7 and 9). For example, population studies may demonstrate that overproduction of key enzymes in E2 synthesis and/or its metabolism is associated with an increased incidence of breast cancer. Underproduction of detoxifying enzymes could have the same associations.
The presentations to follow will focus on each of the key biologic mechanisms described above. The presenters will integrate the individual steps and pathways and utilize a common pathway overview schemata to focus attention on the relative place of each step in the overall metabolic process.
|
NOTES |
|---|
Editor's note: Dr. Santen is a consultant with Eli Lilly and Co. (Evansville, IN) and is conducting research with Novartis Pharmaceuticals Corporation (East Hanover, NJ).
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Guasparri, S. A. Keller, and E. Cesarman KSHV vFLIP Is Essential for the Survival of Infected Lymphoma Cells J. Exp. Med., April 5, 2004; 199(7): 993 - 1003. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||