GPER‐mediated regulation of nuclear Akt/FOXO3a signaling (795.1)

Abstract

In addition to its genomic effects, the steroid hormone estrogen has been shown to mediate rapid signaling events in diverse cell types, including breast cancer cells. These effects are, in part, mediated through its canonical soluble nuclear receptor, ERα. However, a novel estrogen receptor known as GPER (previously termed GPR30) has been demonstrated to activate multiple signaling cascades in response to estrogen. We previously established that PI3Kinase‐mediated production of PIP3 in the nucleus is initiated by estrogen‐mediated stimulation of GPER. The mechanism of this activation and its downstream effects are currently not well understood. Here we describe that rapid signaling through GPER activates PI3Kinase leading to the inactivation and translocation of the proapoptotic protein FOXO3a, resulting in its translocation from the nucleus to the cytoplasm. This activation is mediated by both estrogen and the GPER‐selective agonist G‐1, and occurs via the transactivation of EGFR leading to the activation of the p110alpha subunit of PI3K and subsequent AKT‐mediated phosphorylation of FOXO3a. The nuclear exclusion of FOXO3a by GPER activation suggests GPER signaling results in prosurvival cellular effects in breast cancer cells. Grant Funding Source: NIH