Uterine Deficiency Attenuates Endometrial Hyperplasia and Cancer and Prolongs Lifespan in a Loss-of-Function-Induced Cancer Model.

The expression of members of the progesterone receptor membrane component (PGRMC) family, particularly PGRMC1, is elevated in diverse types of cancers, particularly those of the female reproductive system. While xenograft tumor studies using human transformed cell lines in immunocompromised mice have suggested that enhances tumor growth and chemoresistance, the exact role of members of the PGRMC family in cancer development in vivo remains unclear. In this study, we examined the effect of deleting on the development of endometrial hyperplasia and cancer using a murine () conditional loss-of-function model. We previously established that PGRMCs are cell survival factors that are required for normal estrogen-induced uterine epithelial cell proliferation and normal female fertility. The deletion of reduced the incidence and severity of endometrial hyperplasia and cancer in mice with conditional -heterozygous uteri and increased lifespan in mice with conditional -knockout uteri. Mechanistically, the deletion of decreased uterine glandular epithelial cell proliferation. loss-of-function-induced endometrial hyperplasia and cancer elevated uterine inflammation, but this was not impacted by PGRMC2 deficiency. This study identifies PGRMC2 as a potential therapeutic target to be inhibited in the treatment of endometrial hyperplasia and cancer, particularly where PTEN activity is reduced due to gene mutation or loss.