Diseases of the female reproductive system are a serious and prevalent health problem in modern society. These include ovarian and uterine cancer, endometriosis, premature reproductive aging, and pregnancy loss. These maladies have diverse contributing factors including genetic predisposition and environmental exposures. A better understanding of the genetic and molecular bases of these diseases will undoubtedly improve our ability to predict susceptibility, improve early diagnosis, and develop treatments. In previous work, we developed genetically engineered mice containing mutations in a DNA repair gene called MLH1 that exist in a subset of people. These mice exhibited premature fertility loss that was linked to endometrial hyperplasia (EH) , a precursor to uterine cancer, the 4th most common cancer in women. Inherited defects in MLH1 cause Lynch Syndrome, which predisposes to cancers colorectal and uterine cancer. We hypothesize that EH in our mouse model is caused by the defect in DNA repair that leads to secondary mutations in genes that render cells susceptible to eventually forming tumors. We propose to test this using an advanced culture system called organoids (3 dimensional clusters of cells that resemble the organization of a tissue, in this case, the uterus) that can greatly simplify and accelerate studies into how uterine cancer evolves and how intermediate stages (such as EH) manifest as premature fertility loss.