Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice.
Tamoxifen (TAM), the primary treatment for estrogen receptor (ER)-positive breast cancer, has been associated with an increased incidence of endometrial cancer in postmenopausal, but not premenopausal women. TAM elicits a partial ER-mediated uterotrophic response in immature rodents when compared with ethynylestradiol (EE), a potent ER agonist. However, cotreatment with 1000 microg/kg TAM antagonizes the uterotrophic effect induced by 30 microg/kg EE. To further investigate the anti-uterotrophic activity of TAM, immature, ovariectomized C57BL/6 mice were treated with a single oral dose of EE, TAM, EE+TAM, or vehicle, and harvested at 2, 4, 8, 12, 18, and 24 h or after three daily treatments at 72 h. Significant increases in uterine wet weight (UWW) were observed at 18 h for EE, TAM, and the mixture. However, mixture induction of UWW was significantly lower when compared with EE-induced uterotrophy at 72 h. This inhibitory effect is also reflected in decreases in luminal circumference, yet EE-induced luminal epithelial cell height was unaffected by cotreatment with TAM. Gene expression analysis using a 2 x 2 factorial cDNA microarray study design identified 2518 differentially expressed genes following EE treatment alone. However, only 290 EE-elicited gene expression changes were affected by TAM cotreatment, in a manner consistent with the anti-estrogenic response. These data suggest that TAM antagonism of EE-induced UWW increase involves the selective inhibition of EE-induced genes.
Fong
Cora J
CJ
Department of Biochemistry and Molecular Biology, Michigan State University, 501 Biochemistry Building, Wilson Road, East Lansing, Michigan 48824-1319, USA.
Burgoon
Lyle D
LD
Williams
Kurt J
KJ
Jones
A Daniel
AD
Forgacs
Agnes L
AL
Zacharewski
Timothy R
TR
D000375:Aging / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology
D013629:Tamoxifen; C016601:afimoxifene; D004997:Ethinyl Estradiol