Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms

Abstract

Breast cancer is the most common malignancy among women worldwide. Various studies indicate that prolonged exposure to elevated levels of estrogens is associated with development of breast cancer. Both estrogen receptor-dependent and independent mechanisms can contribute to the carcinogenic effects of estrogens. Among them, the oxidative metabolism of estrogens plays a key role in the initiation of estradiol-induced breast cancer by generation of reactive estrogen quinones as well as the associated formation of oxygen free radicals. These genotoxic metabolites can react with DNA to form unstable DNA adducts which generate mutations leading to the initiation of breast cancer. A variety of endogenous and exogenous factors can alter estrogen homeostasis and generate genotoxic metabolites. The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes (CYP19, CYP1B1) but also through the induction of various cytoprotective enzymes (eg, SOD3, NQO1, glutathione S-transferases, OGG-1, catechol-O-methyltransferases, CYP1B1A, etc.) that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.

Keywords: breast carcinogenesis; depurinating estrogen–DNA adducts; dietary phytochemicals; nuclear factor erythroid 2-related factor 2; reactive estrogen quinones.

Figure 1

Schematic representation of major metabolic pathways involved in breast cancer initiation by estrogens. Abbreviation: CYP, cytochrome P450.

Figure 2

Schematic representation of the Nrf2–ARE pathway activated by phytochemicals. Curcumin, sulforaphane, and green tea catechins are capable of inhibiting the formation of ROS and estrogen genotoxic metabolites such as catechol estrogens, semiquinones, and mutagenic/reactive estrogen quinones by inducing several cytoprotective enzymes such as UDP-GTs, SULTs, NQO1, GSTs, SOD3, and OGG1 through activation of the Nrf2–ARE pathway. OGG1 is the rate-limiting enzyme of the DNA base excision repair pathway implicated in the removal of 8-hydroxydeoxyguanosine adducts from DNA. Notably, the catechol-O-methyltransferase enzyme, which catalyzes the methylation of catechol estrogens to nongenotoxic methoxyestrogens, blocking their further oxidation to semiquinones and mutagenic quinones, is not represented because it is induced by phytochemicals through Nrf2–ARE-independent mechanisms. Abbreviations: ARE, antioxidant responsive elements; CYP, cytochrome P450; GST, glutathione S-transferase; Nrf2, nuclear factor-erythroid 2-related factor 2; NQO1, quinone reductase; OGG1, 8-oxoguanine DNA glycosylase; SULT, sulfotransferase; UDP-GT, UDP-glucuronosyltransferase.