Chapter 3: 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. [J Natl Cancer Inst Monogr 2000;27:67-73]For a substantial fraction of breast cancer cases in women, well-established risk factors, revealed by epidemiologic studies, include early age at menarche, late first full-term pregnancy, nulliparity, late menopause, family history of breast cancer, socioeconomic status, and perhaps estrogen replacement therapy (1-5). A common thread linking these factors is cumulative, excessive lifetime exposure to estrogen, suggesting that this ex-

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

“…The ability of estrogen metabolites (i.e., CE-Qs) to bind to DNA, leading to the formation of depurinating adducts and DNA damage, has been demonstrated. 6,7,8 The fact that the same transformation phenotypes and similar genomic alteration profiles are seen in human breast epithelial cells treated with either estrogen metabolites or well-defined chemical carcinogens is also evidence for the mutagenic effect of estrogen. 37 Furthermore, breast cancer progression was found to be associated with an increasing frequency of DNA DSB suggested to result from the carcinogenic effect of estrogen-induced ROS.…”

“…9,10 In addition, the generation of reactive oxidative species (ROS) during the conversion of CE-SQ to CE-Qs can also lead to oxidative DNA damage. 6,10 To examine whether these various steps in estrogen metabolism were of significance in breast tumorigenesis and to gain an insight into the initiating role of estrogen during breast tumorigenesis, we carried out a multigenic case-control study to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism, namely those that directly detoxify CE, thus avoiding the subsequent stages of CE metabolism, and those that protect against the effects of ROS generated during the conversion of CE-SQ to CE-Qs or detoxify CE-Qs. The genes examined were catechol-O-methyltransferase (COMT), sulfotransferase 1A1 (SULT1A1), and UDP-glucuronosyltransferase 1A1 (UGT1A1), involved in CE detoxification by, respectively, methylation, sulfation, or glucuronidation, manganese superoxide dismutase (MnSOD), involved in protection against ROS-mediated oxidation, and GSTM1 and GSTT1, 2 of the glutathione S-transferase (GST) superfamily, involved in CE-Q inactivation.…”

“…No single carcinogen has been identified conclusively as causing the DNA damage responsible for breast cancer initiation. 6 Estrogen has attracted considerable attention recently because that there is evidence that it can cause DNA damage and mutation. 6 -8 In this initiating mechanism, a critical role is played by the oxidative metabolism of estrogen, which occurs in 2 stages, first to the 4-hydroxyestradiol form of catechol estrogen (CE), then, via the E2-3,4-semi-quinones (CE-SQ), to further oxidized metabolites, the E2-3,4-quinones (CEQs), because in vitro experiments have shown that CE-Qs can bind to DNA to form adducts, leading to DNA depurination, the major type of genetic damage implicated in mutation and strand break of DNA during tumorigenesis.…”

Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

“…Oxidation of native estrogens to the 2-hydroxylated CEs produces a stable, non-carcinogenic metabolite. On the other hand, generation of 4-hydroxylated CEs, particularly 4-hydroxylated estrone (4-OHE 1 ) is associated with the development of estrogensensitive cancers via metabolic redox cycling [17,18]. One possible mechanism for the genotoxicity of the catechol estrogens is the generation of electrophilic metabolites that react with DNA to form depurinating DNA adducts, which ultimately leads to cancer [19].…”

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women

“…Breast cancer is the second most frequent cancer in Korean women and its incidence is increasing (Yoo et al, 1998). Lifetime cumulative exposure to oestrogens is known as the most important risk factor for breast cancer (Yager, 2000). A variety of different enzymes are involved in the synthesis of oestrogen from cholesterol and further metabolism of oestrogen (Thompsen and Ambrosone, 2000).…”