In conclusion, we have revealed a novel function of GPER activation, namely the inactivation of FOXO3a, a consequence of which may be the enhanced survival of breast cancer cells being targeted with anti-hormone therapies (SERMs and SERDs), which through their activation of GPER results in FOXO3a downregulation and inhibition of proapoptotic signaling, in opposition to their intended and primary functions in targeting ERα. This evidence concerns the gene ESR1 and breast carcinoma.