Molecular characterization of Wdr13 knockout female mice uteri: a model for human endometrial hyperplasia

Abstract

Endometrial hyperplasia (EH) is a condition where uterine endometrial glands show excessive proliferation of epithelial cells that may subsequently progress into endometrial cancer (EC). Modern lifestyle disorders such as obesity, hormonal changes and hyperinsulinemia are known risk factors for EH. A mouse strain that mimics most of these risk factors would be an ideal model to study the stage wise progression of EH disease and develop suitable treatment strategies. Wdr13, an X-linked gene, is evolutionarily conserved and expressed in several tissues including uteri. In the present study, Wdr13 knockout female mice developed benign proliferative epithelium that progressed into EH at around one year of age accompanied by an increase in body weight and elevated estradiol levels. Molecular characterization studies revealed increase in ERα, PI3K and a decrease in PAX2 and ERβ proteins in Wdr13 mutant mice uteri. Further, a decrease in the mRNA levels of cell cycle inhibitors, namely; p21 and cyclin G2 was seen. Leukocyte infltration was observed in the uterine tissue of knockout mice at around 12 months of age. These physiological, molecular and pathological patterns were similar to those routinely seen in human EH disease and demonstrated the importance of WDR13 in mice uterine tissue. Thus, the genetic loss of Wdr13 in these mice led to mimicking of the human EH associated metabolic disorders making Wdr13 knockout female mice a potential animal model to study human endometrial hyperplasia.