The ovarian steroid hormones, estrogen (E2) and progesterone (P4), are essential regulators of uterine biology. The imbalance of these ovarian steroid hormones leads to uterine diseases such as endometrial cancer, endometriosis, and infertility. Mitogen-inducible gene 6 (MIG-6) is an adaptor protein. MIG-6 mediates P4 signaling and acts as a tumor suppressor during endometrial tumorigenesis in both humans and mice. In previous studies, we developed the conditional knockout of Mig-6 in all uterine compartments (pgr(cre/+)Mig-6(f/f); Mig-6(KO)) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2f(cre/+)Mig-6(f/f); Mig-6(EP)(-KO)) mice. Both mouse models developed endometrial hyperplasia and E2-dependent endometrial cancer. P4 treatment significantly decreases aberrant epithelial proliferation and AKT signaling in Mig-6(EP)(-KO) mice but not in Mig-6(KO) mice. In the present study, we identified a calcium-dependent phospholipase A2 (cPla2) as one of the genes down-regulated by Mig-6 in the uterus. We performed immunohistochemistry and Western Blot analysis to investigate the regulation of cPLA2 by MIG-6 as well as determine the expression patterns of cPLA2 in the uterus. While the expression of cPLA2 was stronger at the uterine epithelial cells of Mig-6(KO) and Mig-6(EP)(-KO) mice compared to control mice, P4 suppressed the expression of cPLA2 in Mig-6(EP)(-KO) mice but not in Mig-6(KO) mice. To determine the ovarian steroid hormone regulation of cPLA2, we examined the expression of cPLA2 in ovariecto-mized control, Mig-6(KO), Mig-6(EP)(-KO), and PRKO mice treated with P4 or E2. After P4 treatment, cPLA2 expression was remarkably reduced in Mig-6(EP)(-KO) mice but not in Mig-6(KO) mice. However, the expression of cPLA2 was not changed in PRKO mice. Our results identified cPLA2 as a novel target of MIG-6 in the murine uterus and identified its important role during endometrial tumorigenesis. (C) 2019 Elsevier Inc. All rights reserved.