Endogenous estrogens as carcinogens through metabolic activation
- PMID: 10963620
- DOI: 10.1093/oxfordjournals.jncimonographs.a024245
Endogenous estrogens as carcinogens through metabolic activation
Abstract
A common thread linking the main risks for developing breast cancer in women is cumulative, excessive exposure to estrogen. The standard paradigm to account for this association focuses on increased cell proliferation caused by estrogen through estrogen receptor-mediated signal transduction accompanied by increased probability for mutation to occur during DNA synthesis. This chapter provides an overview of the mounting evidence, provided from cell culture and whole animal experimental studies, in support of a role for the oxidative metabolites of estrogen, in particular, the catechol estrogens, in the development of estrogen carcinogenesis. This provides a paradigm for how estrogens may contribute to the development of human breast cancer. The chapters that follow will fill in the details. Evidence shows that the catechols themselves are signaling molecules that work through the estrogen receptor. In addition, upon further oxidation, the catechols can give rise to reactive quinones capable of forming direct adducts with glutathione and purines in DNA and of redox cycling to generate reactive oxygen species that can cause oxidative damage. Estradiol and estrone, as well as their 4-hydroxy catechols, are carcinogenic in the Syrian golden hamster kidney, and ethinyl estradiol is a strong promoter of hepatocarcinogenesis in the rat. Increased oxidative DNA damage has been detected in target tissues after estrogen treatment in both animal model systems. Furthermore, several recent molecular epidemiologic studies have found that a polymorphism associated with a low-activity form of catechol-O-methyltransferase, an enzyme involved in the inactivation of catechol estrogens, is associated with an increased risk for developing breast cancer. The increased risk is observed in certain women, although the studies are not consistent on which subgroup of women (e.g., premenopausal or postmenopausal) is at increased risk, and one study detected no increased risk. Reasons for such discrepancies are discussed in light of factors, such as genetic polymorphisms and environmental/lifestyle susceptibility factors, which control the tissue-specific balance within cells among the estrogen metabolites. It is concluded that such factors will have to be identified through additional mechanistic studies and that, as they are identified, they can be incorporated into future molecular epidemiologic studies designed to determine their actual impact on cancer risk in human populations.
Similar articles
-
Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention--A review.Steroids. 2015 Jul;99(Pt A):56-60. doi: 10.1016/j.steroids.2014.08.006. Epub 2014 Aug 24. Steroids. 2015. PMID: 25159108 Free PMC article. Review.
-
The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites.Endocrinology. 1993 Feb;132(2):577-83. doi: 10.1210/endo.132.2.8381068. Endocrinology. 1993. PMID: 8381068
-
Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells.Carcinogenesis. 2011 Aug;32(8):1285-93. doi: 10.1093/carcin/bgr109. Epub 2011 Jun 10. Carcinogenesis. 2011. PMID: 21665890 Free PMC article.
-
Estrogen metabolism by conjugation.J Natl Cancer Inst Monogr. 2000;(27):113-24. doi: 10.1093/oxfordjournals.jncimonographs.a024234. J Natl Cancer Inst Monogr. 2000. PMID: 10963623 Review.
-
The molecular etiology and prevention of estrogen-initiated cancers: Ockham's Razor: Pluralitas non est ponenda sine necessitate. Plurality should not be posited without necessity.Mol Aspects Med. 2014 Apr;36:1-55. doi: 10.1016/j.mam.2013.08.002. Epub 2013 Aug 30. Mol Aspects Med. 2014. PMID: 23994691 Free PMC article. Review.
Cited by 105 articles
-
Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas.Cancers (Basel). 2020 Mar 13;12(3):669. doi: 10.3390/cancers12030669. Cancers (Basel). 2020. PMID: 32183012 Free PMC article.
-
New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases.Acta Pharm Sin B. 2020 Jan;10(1):91-104. doi: 10.1016/j.apsb.2019.11.016. Epub 2019 Dec 2. Acta Pharm Sin B. 2020. PMID: 31998606 Free PMC article. Review.
-
Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy.J Clin Med. 2020 Jan 17;9(1):245. doi: 10.3390/jcm9010245. J Clin Med. 2020. PMID: 31963437 Free PMC article.
-
APOBEC3B expression in breast cancer cell lines and tumors depends on the estrogen receptor status.Carcinogenesis. 2020 Aug 12;41(8):1030-1037. doi: 10.1093/carcin/bgaa002. Carcinogenesis. 2020. PMID: 31930332
-
The estrogen effect; clinical and histopathological evidence of dichotomous influences in dogs with spontaneous mammary carcinomas.PLoS One. 2019 Oct 25;14(10):e0224504. doi: 10.1371/journal.pone.0224504. eCollection 2019. PLoS One. 2019. PMID: 31652293 Free PMC article.
Publication types
MeSH terms
Substances
Grant support
LinkOut - more resources
-
Full Text Sources
-
Other Literature Sources
-
Medical