Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine

Abstract

A growing number of studies indicate that breast cancer initiation is related to abnormal estrogen oxidation to form an excess of estrogen-3,4-quinones, which react with DNA to form depurinating adducts and induce mutations. This mechanism is often called estrogen genotoxicity. 4-Catechol estrogens, precursors of the estrogen-3,4-quinones, were previously shown to account for most of the transforming and tumorigenic activity. We examined whether estrogen-induced transformation can be reduced by inhibiting the oxidation of a 4-catechol estrogen to its quinone. We demonstrate that E6 cells (a normal mouse epithelial cell line) can be transformed by a single treatment with a catechol estrogen or its quinone. The transforming activities of 4-hydroxyestradiol and estradiol-3,4-quinone were comparable. N-Acetylcysteine, a common antioxidant, inhibited the oxidation of 4-hydroxyestradiol to the quinone and consequent formation of DNA adducts. It also drastically reduced estrogen-induced transformation of E6 cells. These results strongly implicate estrogen genotoxicity in mammary cell transformation. Since N-acetylcysteine is well tolerated in clinical studies, it may be a promising candidate for breast cancer prevention.

Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

“…In addition, these adducts could be used to investigate the ability of putative preventive compounds to reduce the risk of developing NHL. Based on this study, one could speculate that minimizing the formation of catechol estrogen quinones and/or their reaction with DNA , 2009b, Zahid et al 2007, Venugopal et al 2008 should reduce the risk of developing NHL. These preventive effects have been seen in vitro (Zahid et al 2007) and in cell cultures (Venugopal et al 2008) treated with specific putative preventive compounds.…”

Antioxidant Activity of Sulfur and Selenium: A Review of Reactive Oxygen Species Scavenging, Glutathione Peroxidase, and Metal-Binding Antioxidant Mechanisms

“…2 Antioxidant sulfur compounds discussed in this review proliferation [121]. Abnormal estrogen metabolism can result in DNA adducts and mutations that are implicated in breast cancer; however, a recent study suggests the possible use of NAC supplementation for protection against this estrogen genotoxicity [139]. Venugopal and co-workers tested cell viability of mouse epithelial breast cells (E6) exposed to estrogen-3,4-quinones and NAC.…”

“…Venugopal and co-workers tested cell viability of mouse epithelial breast cells (E6) exposed to estrogen-3,4-quinones and NAC. Their studies reveal a significant decrease in adduct formation (63-90% reduction) by NAC, suggesting the possibility for NAC in preventing breast cancer [139]. N-acetylcysteine amide prevents the cytotoxic effects of glutamate by preventing lipid peroxidation, scavenging ROS, and maintaining cellular GSH levels in PC12 cells, which are implicated in neurological disorders such as Parkinson's and Alzheimer's diseases [122].…”

Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants

“…Resveratrol was also found to inhibit the malignant transformation of MCF-10F cells treated with E 2 (58). NAcCys was found to inhibit not only formation of estrogen-DNA adducts, but also transformation of E6 mouse mammary cells treated with 4-OHE 2 or E 2 -3,4-Q (39).…”

“…Two antioxidants have demonstrated great efficiency in keeping the catechol estrogen oxidative pathway balanced in the MCF-10F human breast epithelial cell line and in the E6 mouse mammary cell line (39,(58)(59)(60)(61). The antioxidant effect of NAcCys in reducing formation of estrogen-DNA adducts in MCF-10F cells treated with 4-OHE 2 (60) is due to the reaction of NAcCys with E 2 -3,4-Q and the reduction of E 2 -3,4-semiquinone to 4-OHE 2 (57).…”