Loss of HOXA10 causes endometrial hyperplasia progressing to endometrial cancer

Endometrial cancer is the fourth most common malignancy in women and the precursor lesion is endometrial hyperplasia. HOXA10 is a transcription factor that plays key roles in endometrial functions such as the endowment of receptivity, embryo implantation, and trophoblast invasion. Herein, using testicular transgenesis, we developed transgenic mice that expressed an shRNA against HOXA10 and observed that in these animals there was nearly 70% reduction in the expression of HOXA10. We termed these animals as HOXA10 hypomorphs and observed that downregulation of HOXA10 led to the development of endometrial hyperplasia and most animals developed well-differentiated endometrial adenocarcinoma with age. There was an increased proliferation of the uterine glands and stromal cells in the hypomorphs along with a gain of OVGP1 expression and increased levels of ERα and ERβ. In parallel, there was increased expression of Wnt4 and β-Catenin, SOX9 and YAP1. We propose that chronic reduction in HOXA10 expression disrupts multiple pathways in the uterus that aids in the development of endometrial hyperplasia which progresses to endometrial cancer with age.