Abstract
BackgroundEstrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis.MethodsFemale ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2.ResultsThe expression of OGG1 was suppressed in mammary tissues and in mammary tumors of rats treated with E2. Expression of NRF2 was also significantly suppressed in E2-treated mammary tissues and in mammary tumors. Vitamin C or BHA treatment prevented E2-mediated decrease in OGG1 and NRF2 levels in the mammary tissues. Chromatin immunoprecipitation analysis confirmed that antioxidant-mediated induction of OGG1 was through increased direct binding of NRF2 to the promoter region of OGG1. Studies using silencer RNA confirmed the role of OGG1 in inhibition of oxidative DNA damage.ConclusionsOur studies suggest that antioxidants Vit C and BHA provide protection against oxidative DNA damage and E2-induced mammary carcinogenesis, at least in part, through NRF2-mediated induction of OGG1.
Highlights
Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis
We present evidence that antioxidants, vitamin C (Vit C)- and butylated hydroxyanisole (BHA)-mediated induction of nuclear factor erythroid 2-related factor 2 (NRF2) regulates 8-Oxoguanine DNA glycosylase (OGG1) which is involved in the inhibition of E2-induced oxidative DNA damage and possibly breast carcinogenesis in the rat model of breast cancer
Estrogen treatment inhibits OGG1 expression We investigated the effect of E2 treatment on the mRNA expression of OGG1 during early exposure time to estrogen (7 days) and during neoplastic (240 days) stages of breast cancer development in female August Copenhagen Irish (ACI) rats
Summary
Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. In E2-induced breast carcinogenesis, oxidative stress produced by redox cycling between catechol estrogens and estrogen quinones is implicated to play an important role [8,9]. 8-Hydroxydeoxyguanosine (8OHdG) is one of the most commonly formed DNA lesions produced in response to E2-induced oxidative stress and is considered as a cellular marker for both oxidative stress and oxidative DNA damage [3,4,5]. We have earlier reported that two known prototypic antioxidants Vit C and BHA can inhibit E2-mediated breast cancer development in female ACI rats [2,5,7]. The tumors that develop in this animal model are estrogen dependent, aneuploid and exhibit genomic instability [14,15,16,17,18,19]
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