Uterine Epithelial Cells Specific Estrogen Receptor alpha-Dependent Gene Expression Profiles in Response to Estrogen

Estrogens stimulate hypertrophy and hyperplasia in the uterus and exert their activity through estrogen receptor α (ERα). A uterine epithelial ERα conditional knockout mouse model (Wnt7aCre+;Esr1f/f or cKO) demonstrated that ERα in the epithelial cells was dispensable for an early uterine proliferative response to 17β-estradiol (E2), but required for subsequent uterine biological responses. We compared the gene expression profile in the uterus after E2 treatment in the cKO samples with WT samples. We found that approximately 25% of the genes differentially expressed at 2 h were epithelial ERα independent, as they were preserved in the cKO, indicating they are mediated from the stroma and sufficient to promote initial proliferative responses. However, more than 90% of the differentially expressed transcripts at 24 h were absent in the cKO, indicating the majority of later transcriptional regulation required epithelial ERα and suggesting the loss of regulation of these later transcripts results in the blunted growth response 3 days after treatment. These transcription profiles correlate with our previous biological responses, in which the initial proliferative response is independent of epithelial ERα but dependent on stromal ERα, yet epithelial ERα is essential for subsequent tissue responsiveness. These analyses are now allowing for in vivo determination of the cell specific actions of ERα in the female reproductive tract. The uterine samples were collected from ovariectomized female reproductive tract epithelial ERα knockout (cKO) at 24 h after vehicle (saline) treatment and at 2 and 24 h 17beta-estradiol (0.25 ug/mouse) treatment. Each experimental group contains 3 replicates. Gene expression analysis was conducted by using Agilent Whole Mouse Genome 4×44 multiplex format oligo arrays (no. 014868; Agilent Technologies, Santa Clara, CA).