Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers

Abstract

Experiments on estrogen metabolism, formation of DNA adducts, mutagenicity, cell transformation and carcinogenicity have led to and supported the hypothesis that the reaction of specific estrogen metabolites, mostly the electrophilic catechol estrogen-3,4-quinones, with DNA can generate the critical mutations to initiate breast and other human cancers. Analysis of depurinating estrogen-DNA adducts in urine demonstrates that women at high risk of, or with breast cancer, have high levels of the adducts, indicating a critical role for adduct formation in breast cancer initiation. Men with prostate cancer or non-Hodgkin lymphoma also have high levels of estrogen-DNA adducts. This knowledge of the first step in cancer initiation suggests the use of specific antioxidants that can block formation of the adducts by chemical and biochemical mechanisms. Two antioxidants, N-acetylcysteine and resveratrol, are prime candidates to prevent breast and other human cancers because in various M in vitro and in vivo experiments, they reduce the formation of estrogen-DNA adducts.

Figure 1

Major metabolic pathway in cancer initiation by estrogens.

Figure 2. Formation, metabolism and DNA adducts of estrogens

Activating enzymes and depurinating DNA adducts are in red and protective enzymes are in turquoise. N-acetylcysteine (NAcCys, shown in blue) and resveratrol (Resv, purple) indicate the various points where NAcCys and Resv could improve the balance of estrogen metabolism and minimize the formation of depurinating DNA adducts.

Figure 3. Expression of estrogen-metabolizing enzymes in the human breast

Reproduced with permission from [60].

Figure 4. Structures of the depurinating N3Ade and N7Gua adducts formed by reaction of the catechol quinones of hexestrol and DES with DNA

DES: Diethylstilbestrol; HES: Hexestrol.

Figure 5. Depurinating estrogen–DNA adducts in urine of healthy women, high-risk women and women with breast cancer

(A) First study. (B) Second study [81,82]. In the ratio of depurinating estrogen–DNA adducts to the sum of their respective estrogen metabolites and conjugates, the 4-catechol estrogen–DNA adducts account for more than 98% of the value of the ratio.

Figure 6. Levels of the estrogen–DNA adducts in urine samples from men with and without prostate cancer

Reproduced with permission from [84].

Figure 7

Structures of antioxidant compounds, N-acetylcysteine and resveratrol.

Figure 8. Levels of depurinating estrogen–DNA adducts in culture medium from cells treated with 4-OHE₂, with or without Resv

The levels of DNA adducts in Resv-treated cells were significantly lower than those in the cells not treated with Resv (p < 0.05) as determined by analysis of variance. Reproduced with permission from [94].