Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus.

Fabiola F Mehta,Kenneth S Korach,John P Lydon,Jieun Son,Eunjung Jang,Sang-Hyuk Chung,Sylvia C Hewitt

doi:10.18632/oncotarget.8159

Fabiola F Mehta, Kenneth S Korach + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.8159

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Abstract

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor α (ERα) in the female reproductive tracts. Using knock−in mouse models expressing ERα mutants, we determined that the DNA−binding domain (DBD) and AF2 domain of ERα were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ERα AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ERα DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ERα. Epithelial ERα was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.

Highlights

Progesterone (P4) and estradiol (E2) are major ovarian steroid hormones crucial for the development and homeostasis of the female reproductive tract [1]
Under the same hormonal condition, epithelial progesterone receptor (PR) was necessary for P4 to suppress E2−induced epithelial cell proliferation in the cervix and vagina, but dispensable in the uterus (Figure 2)
This discrepancy may be due to differences in treatment design (P4 for 3 days and E2+P4 for 1 day vs. E2+P4 for 7 days), E2 doses (50 ng vs. 1 μg), mouse genetic background (B6.SJL.129 mixed vs. FVB) and/or housing environment

Summary

INTRODUCTION

Progesterone (P4) and estradiol (E2) are major ovarian steroid hormones crucial for the development and homeostasis of the female reproductive tract (i.e., uterus, cervix, and vagina) [1]. Reporter assays using isolated regulatory sequences of the PGR gene have implicated both classical and tethering mechanism in the transcriptional activation of PGR in MCF7 breast cancer cells [6,7,8,9] It is unclear whether it is relevant to the normal female reproductive tract and whether both pathways are important in the natural chromatin context. Stromal ERα is required for squamous epithelial cell proliferation in the cervix and vagina [14]. Using knock−in mice expressing mutant ERα lacking activities of DBD, AF1, or AF2, we show that all three domains are required for upregulation of Pgr in the cervical epithelium and vagina. Using epithelial Pgr−deficient mice, we demonstrate that epithelial PR is required for P4−induced apoptosis and suppression of cell proliferation in the cervical and vaginal epithelium. Our results are the first to show different functions and regulation of epithelial PR in the cervix, vagina, and uterus under the same hormonal condition

RESULTS

DISCUSSION

Ethics statement

Findings

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