Assessment of anti-estrogenic activity of tamoxifen in transgenic mice expressing an enhanced green fluorescent protein gene regulated by estrogen response element.
Tamoxifen is an anti-estrogenic agent for the treatment of breast cancer, while exhibiting estrogenic activity in such tissues as the uterus. This study aimed to test whether these opposite properties of tamoxifen in the uterus can be evaluated separately in vivo. We employed two transgenic murine models named, respectively, the ERE-EGFP Ar+/+ mouse and ERE-EGFP Ar-/- mouse. Both types of mice possess an enhanced green fluorescent protein (EGFP) gene regulated by four copies of estrogen response elements (EREs), while the latter lacks a functional aromatase gene, which encodes an enzyme catalyzing conversion of androgens to estrogens. Tamoxifen clearly exhibited estrogenic activity in the uteri of ERE-EGFP Ar-/- mice, as it caused uterine wet weight gain and E2-target gene induction, as 17beta-estradiol (E2) did. However, tamoxifen did not enhance the EGFP expression in ERE-EGFP Ar-/- mice, although E2 induced it significantly. In ERE-EGFP Ar+/+ mice, tamoxifen suppressed the EGFP expression in a time- and dose-dependent manner. Thus, the present study demonstrated that estrogenic and anti-estrogenic activities of tamoxifen can be evaluated by using ERE-EGFP Ar-/- and ERE-EGFP Ar+/+ mice, respectively. Furthermore, these animal models are useful to select and evaluate estrogenic and anti-estrogenic activities of chemical compounds.
Hayashi
Yoshihiro
Y
Department of Pathology, School of Medicine, Kochi University, Oko-cho, Nankoku, Kochi 783-8505, Japan.
Toda
Katsumi
K
Saibara
Toshiji
T
Okada
Teruhiko
T
Enzan
Hideaki
H
D000818:Animals; D003176:Complement C3 / Q000187:drug effects; D011415:Complement Factor B / Q000494:pharmacology; D004032:Diet; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000096:biosynthesis* / Q000235:genetics; D007781:Lactoferrin / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020218:Response Elements; D013629:Tamoxifen / Q000494:pharmacology*; D013737:Testis / Q000187:drug effects; D015533:Transcriptional Activation; D014599:Uterus / Q000187:drug effects
D003176:Complement C3; D004965:Estrogen Antagonists; D004967:Estrogens; C485184:enhanced green fluorescent protein; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D004958:Estradiol; D007781:Lactoferrin; D011415:Complement Factor B