Reduction of estrogen-induced transformation of mouse mammary epithelial cells by N-acetylcysteine.
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.
Venugopal
Divya
D
Eppley Institute for Research in Cancer and Allied Diseases, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, United States.
Zahid
Muhammad
M
Mailander
Paula C
PC
Meza
Jane L
JL
Rogan
Eleanor G
EG
Cavalieri
Ercole L
EL
Chakravarti
Dhrubajyoti
D
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003114:Colony-Forming Units Assay; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity; D002393:Estrogens, Catechol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D011905:Genes, ras; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation
D018736:DNA Adducts; D002393:Estrogens, Catechol; C116356:catechol estrogen 3,4-quinone; D004958:Estradiol; C014036:4-hydroxyestradiol; D000111:Acetylcysteine