Estrogen sensing by GPER1 activates PI3K/mTOR to promote gender dimorphism in liver growth and cancer

Liver cancer is a common cause of cancer death, with a male-predominant incidence due, in part, to increased estrogen levels in cirrhotic patients. It is unknown, however, how estrogen is sensed to influence this process. Here, we show that estrogen activates the G protein-coupled estrogen receptor 1 (GPER1), expressed in hepatocytes, to enhancing hepatocyte size, cell cycle progression and cell proliferation, thereby increasing liver growth in zebrafish larvae and adults. GPER1 stimulation activates PI3K/mTOR signaling, and mTOR is essential for both normal and regenerative organ growth. Genetic loss of GPER1 diminishes and estrogen exposure accelerates chemical carcinogenesis, specifically in males. Chemical inhibition of GPER1 significantly reduces cancer incidence and progression in a gender-specific fashion. Our studies identify GPER1 as a hepatic estrogen sensor that mediates gender dimorphic growth, mTOR activation, and can serve as a therapeutic target for liver cancer treatment. Overall design: RNA-Seq analysis of control DMSO-treated livers and ß-Estradiol exposed livers were examined.