Table 1.

Chemopreventive agents capable of maintaining balanced estrogen metabolism through Nrf2-dependent and independent mechanisms

Chemopreventive agents	Effect	Nrf2-dependent mechanisms	Nrf2-independent mechanisms	References
Isothiocyanates eg, sulforaphane (SFN), dithiolethiones, triterpenoids, genistein, resveratrol, BHT, etc.	Protection against oxidative DNA damage; decreased formation of depurinating estrogen–DNA adduct derived from catechol estrogen-induced and inhibition of E2-induced breast cancer	Upregulation of antioxidant/detoxifying enzymes NQO1 and GSTs and other cytoprotective proteins	SFN-mediated upregulation of protective enzymes COMTs and GSTA1 and reduction of CYP1B1 protein; inhibition of activating enzyme CYP19 (aromatase) which converts androgens to estrogens by several phytochemicals	[17,18,61,66]
Resveratrol (Res)	Suppression of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCCD) and estradiol-induced neoplastic transformation by blocking depurinating DNA adduct formation	Upregulation of the cytoprotective genes NQO1, SOD3, and OGG1 involved in protection against oxidative DNA damage and inhibition of E2-induced breast cancer	Res-mediated downregulation of catechol estrogens 4-OH-E1(E2) by suppressing expression of TCCD-induced CYP1B1; direct antioxidant activity of Res and reduction of semiquinones back to catechol estrogens; Res-mediated induction of apoptosis in breast cancer cells	[19,22,100]
Resveratrol and NAC	Reduction of the depurinating estrogen–DNA adduct levels that generate mutations involved in E2-mediated breast carcinogenesis	Increased expression of the cytoprotective enzyme NQO1 which reduces the quinones to catechols	Reduced expression of CYP1B1 protein. NAC, furthermore to reducing semiquinones to catechols, directly reacts with the catechol estrogen quinones and is hydrolyzed to cysteine that is involved in the biosynthesis of antioxidant GSH	[20]
Vitamin C or BHA	Protection against E2-mediated oxidative DNA damage	Upregulation of detoxifying and antioxidant enzymes NQO1 and only SOD3	Reversion of E2-mediated expression of various oncogenic micro-RNAs such as miR-93 and miR-153 that inhibit the expression of Nrf2	[21,43,100,101]
Dietary γ-tocopherol (γ-TmT)	Inhibition of E2-induced breast carcinogenesis through regulating E2-metabolizing enzymes, antioxidant response, and PPARγ	Upregulation of several phase 2 detoxifying and antioxidant enzymes such as HO-1, glutamate cysteine ligase, modifier subunit (GCLM), SOD, and CAT that protect against nitrosative and oxidative stress induced by estrogens	γ-TmT activation of PPARγ signaling in cancer cell lines that reduces cell proliferation; reduced expression of inflammatory markers (NF-κB, COX-2, cytokines, PGE2, 8-isoprostane, iNOS); main induction of CYP1A1 over CYP1B1	[62,63]
Melatonin	Increased cell and mitochondrial protection against xenobiotics and endobiotics	Upregulation of antioxidant and detoxifying enzymes mentioned above	Control of inflammatory and prooxidant/antioxidant genes by modulating the expression of NF-κB, AP-1; control of apoptotic signaling in mitochondria; antioxidant effect through reduction of the E2-3,4-semiquinone to 4-OH-E2, scavenging function on NO, peroxinitrite (ONOO–) and several ROS	[23,65,143]
α-Lipoic acid	Protection against oxidative stress and E2-induced breast cancer	Attenuation of age-associated decline in transcriptional activity of Nrf2 and subsequent glutathione synthesis that protects against oxidative stress and carcinogenesis	Recycling of several cellular antioxidants, including coenzyme Q, vitamins C and E, GSH, and chelation of iron and copper	[24,25]
Modified Xiaoyao powder and its active components (quercetin, kaempferol, and atractylenolide II)	Protection against oxidative stress by inducing the Nrf2–NQO1 pathway in human breast cancer cell lines	Induction of the phase 2 detoxifying enzyme NQO1 in MCF-7 cells. NQO1 is a cytosolic flavoenzyme that acts by reducing and detoxifying quinones back to catechols which can be methylated by COMT to form nongenotoxic compounds for mammary tissue		[70]
Cabbage juices and indoles (I3C, DIM)	Protection against E2-mediated breast carcinoginogenes by modulating the expression of the estrogen metabolism key enzymes (CYP1A1, CYP1A12, CYP1B1) in breast epithelial cells	Increased expression of antioxidant and detoxifying enzymes NQO1 and GSTs; reversion of the inhibitory effect of estrogen on cytoprotective enzymes	Preferential modulation of enzymes of the CYP1A1 family involved in estrogen metabolism by binding to AhR; AhR degradation of ER and inhibition of estrogen signaling; binding to ER, competition with E2 and inhibition of E2-dependent gene expression	[71]
4-β-Hydroxywithanolide E from Physalis peruviana	4-β-Hydroxywithanolide E inhibition of tumor growth in female athymic nude mice inoculated with human breast cancer MDA-MB-231 xenografts	Upregulation of cellular antioxidant defense systems such as SOD, CAT, and GSH	4-β-Hydroxywithanolide E-induced apoptosis of MCF-7 cells	[72]
3-phenyl-3-shogaol	Protection against breast cancer and other malignancies by exerting antioxidant, anti-inflammatory and anti-invasive effects	Induction of antioxidant and detoxifying enzymes by modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Keap1	Suppression of breast cancer cell invasion through the modulation of expression of NF-κB-dependent matrix metalloproteinase (MMP-9); inhibition of NF-κB-mediated inflammatory response by significant reduction of the inflammatory mediators and their products	[86]
Pomegranate (PE)	Protection against DMBA-initiated mammary carcinogenesis in female rats	Increased expression of several detoxifying and antioxidant enzymes implicated in the modulation of inflammation and inflammation-associated carcinogenesis	Abrogation of DMBA- mediated inflammatory signaling and mammary tumor cell growth by the inhibition of COX-2 expression, downregulation of HSP90 and other inflammatory mediators by antagonizing the NF-κB pathway	[87]

Abbreviations: AhR, aryl hydrocarbon receptor; AP-1, activator protein 1; ARE, antioxidant responsive elements; BHA, butylated hydroxyanisole; COMT, catechol-O-methyltransferase; COX, cyclooxygenase; CYP, cytochrome P450; DIM, 3,3ʹ-diindolylmethane; DMBA, dimethylbenz(a)anthracene; E1, estrone; E2, estradiol; ER, estrogen receptor; GSH, glutathione; GST, glutathione S-transferase; HSP, heat shock protein; I3C, indole-3-carbinol; iNOS, inducible nitric oxide synthase; NAC, N-acetylcysteine; NF-κB, nuclear factor kappa B; NO, nitric oxide; Nrf2, nuclear factor-erythroid 2-related factor 2; NQO1, quinone reductase; OGG1, 8-oxoguanine DNA glycosylase; PGE2, prostaglandin E2; UDP-GT, UDP-glucuronosyltransferase.