Rapid estrogen signaling negatively regulates PTEN activity through phosphorylation in endometrial cancer cells.

ABSTRACT: Hyperestrogenicity is a risk factor for endometrial cancer. 17?-estradiol (E2) is known to stimulate both genomic and nongenomic estrogen receptor-? (ER?) actions in a number of reproductive tissues. However, the contributions of transcription-independent ER? signaling on normal and malignant endometrium are not fully understood. Phosphatase and tensin homolog (PTEN) is a tumor suppressor that decreases cellular mitosis primarily through negative regulation of the phosphoinositide 3-kinase/AKT signaling axis. PTEN levels are elevated during the E2 dominated, mitotically active, proliferative phase of the menstrual cycle, indicating possible hormonal regulation of PTEN in the uterus. In order to determine if rapid E2 signaling regulates PTEN, we used ER?-positive, PTEN-positive, endometrial cells. We show that cytosolic E2/ER? signaling leads to increased phosphorylation of PTEN at key regulatory residues. Importantly, E2 stimulation decreased PTEN lipid phosphatase activity and caused consequent increases in phospho-AKT. We further demonstrate that cytosolic ER? forms a complex with PTEN in an E2-dependent manner, and that ER? constitutively complexes with protein kinase2-? (CK2?), a kinase previously shown to phosphorylate the C-terminal tail of PTEN. These results provide mechanistic support for an E2-dependent, ER? cytosolic signaling complex that negatively regulates PTEN activity through carboxy terminus phosphorylation. Using an animal model, we show that sustained E2 signaling results in increased phospho-PTEN (S380, T382, and T383), total PTEN, and phospho-AKT (S473). Taken together, we provide a novel mechanism in which transcription-independent E2/ER? signaling may promote a pro-tumorigenic environment in the endometrium.

SUBMITTER: Scully MM 

PROVIDER: S-EPMC4103875 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature