Comparative temporal and dose-dependent morphological and transcriptional uterine effects elicited by tamoxifen and ethynylestradiol in immature, ovariectomized mice.
BACKGROUND
Uterine temporal and dose-dependent histopathologic, morphometric and gene expression responses to the selective estrogen receptor modulator tamoxifen (TAM) were comprehensively examined to further elucidate its estrogen receptor-mediated effects. These results were systematically compared to the effects elicited by the potent estrogen receptor ligand 17alpha-ethynylestradiol (EE) to identify pathways similarly and uniquely modified by each compound.


RESULTS
Three daily doses of 100 microg/kg TAM elicited a dose-dependent increase in uterine wet weight (UWW) in immature, ovariectomized C57BL/6 mice at 72 hrs with concurrent increases in luminal epithelial cell height (LECH), luminal circumference and glandular epithelial tubule number. Significant UWW and LECH increases were detected at 24 hrs after a single dose of 100 microg/kg TAM. cDNA microarray analysis identified 2235 differentially expressed genes following a single dose of 100 microg/kg TAM at 2, 4, 8, 12, 18 and 24 hrs, and at 72 hrs after three daily doses (3 x 24 hrs). Functional annotation of differentially expressed genes was associated with cell growth and proliferation, cytoskeletal organization, extracellular matrix modification, nucleotide synthesis, DNA replication, protein synthesis and turnover, lipid metabolism, glycolysis and immunological responses as is expected from the uterotrophic response. Comparative analysis of TAM and EE treatments identified 1209 common, differentially expressed genes, the majority of which exhibited similar profiles despite a temporal delay in TAM elicited responses. However, several conserved and treatment specific responses were identified that are consistent with proliferation (Fos, Cdkn1a, Anapc1), and water imbibition (Slc30a3, Slc30a5) responses elicited by EE.


CONCLUSIONS
Overall, TAM and EE share similar gene expression profiles. However, TAM responses exhibit lower efficacy, while responses unique to EE are consistent with the physiological differences elicited between compounds.
Fong
Cora J
CJ
Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. fongcora@msu.edu
Burgoon
Lyle D
LD
Williams
Kurt J
KJ
Forgacs
Agnes L
AL
Zacharewski
Timothy R
TR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D013629:Tamoxifen / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D013629:Tamoxifen; D004997:Ethinyl Estradiol