title: Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland.
abstract: Extensive data suggest that estradiol contributes to the development of breast cancer by acting as a mitogen and exerting direct genotoxic effects after enzymatic conversion to 4-hydroxyestradiol (4-OHE2) via cytochrome P450 1B1 (CYP1B1). The mammary gland, ovary, and uterus all express CYP1B1. Overexpression of this enzyme has been associated with an increased risk of breast cancer and blockade might reduce this carcinogenic effect. For this reason, we conducted systematic in vitro and in vivo studies of a CYP1B1 inhibitor, TMS (2,3',4,5'-tetramethoxystilbene). We found that TMS blocked the enzymatic conversion of radiolabeled estradiol to both 2-hydroxyestradiol (2-OHE2) and 4-OHE2, but did not inhibit Cyp1b1 message formation. In vivo studies using mass spectrometry showed that TMS inhibited formation of 2-OHE2 and 4-OHE2 and the resulting estrogen-DNA adducts. To examine its biologic actions in vivo, we investigated whether TMS could block the hyperplastic changes that occur in the developing breast of aromatase-transfected mice. We found that TMS induced a significant reduction of ductal structures in mice less than 6 months in age. In older mice, no reduction in breast morphology occurred. These latter studies uncovered unexpected estrogen agonistic actions of TMS at high doses, including a paradoxical stimulation of breast ductal structures and the endometrium. These studies suggest that the enzyme inhibitory properties of TMS, as well as the effects on developing breast, could implicate a role for TMS in breast cancer prevention, but only in low doses and on developing breast.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Taehyun
authors.initials: T
authors.lastname: Kim
authors.forename: Hoyong
authors.initials: H
authors.lastname: Park
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Atkins
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Rogan
authors.forename: Ercole L
authors.initials: EL
authors.lastname: Cavalieri
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Aiyar
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D049109:Cell Proliferation; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077289:Letrozole; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy / Q000379:methods; D013267:Stilbenes / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C440850:2,4,3',5'-tetramethoxystilbene; D004967:Estrogens; D009570:Nitriles; D013267:Stilbenes; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1