• How Does Estrogen Receptor Signaling Promote Growth of Liver Tumors?

How Does Estrogen Receptor Signaling Promote Growth of Liver Tumors?

The G-protein–coupled estrogen receptor (GPER1) is a hepatic sensor of estrogen that regulates liver growth during development, regeneration, and tumorigenesis, researchers show in a study of zebrafish and human liver published in the May issue of Gastroenterology. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment.

Brightfield and fluorescent images of male and female Tg(fabp10a:GFP) adult zebrafish exposed to DMSO (0.1%) or E2 (10 μmol/L) daily for 6 weeks. Scale bars, 2 mm.

Liver cancer is the second most common cause of cancer death worldwide, and it predominantly affects men. Studies have shown sexually dimorphic responses after hepatectomy—women have a higher rate of liver regeneration. Researchers have searched for sex-specific differences in liver growth. Levels of 17β-estradiol (E2) increase after liver injury and promote liver regeneration in ovariectomized female mice.

E2 signaling is mediated by the nuclear hormone estrogen receptors 1 and 2 (ESR1 and ESR2), which regulate transcription, but also via (GPER1, also known as GPR30). The activities of ESR1 and ESR2 have been widely studied, but little is known about GPER1 signaling in the liver. Originally discovered in breast cancer cells, GPER1 regulates proliferation and relaxation of vascular smooth muscles via extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K), and calcium.

Saireudee Chaturantabut et al investigated the mechanisms of E2 signaling via GPER1 in the regulation of liver growth.

They found that E2 induces cell cycle progression and proliferation in hepatocytes and increases liver size in zebrafish larvae (see figure). Surprisingly, these effects were not mediated by ESR1 or ESR2, but rather by GPER1 activation of PI3K signaling via MTOR. The PI3K–AKT–MTOR pathway regulates the cell cycle and cell and organ size in response to environmental factors .

In zebrafish liver, E2 affected transcriptional programs and metabolites involved in cell cycling and proliferation. The authors concluded that during larval stages, E2 promotes hepatocyte proliferation, cell cycle progression, and overall liver size via GPER1.

GPER1 promoted sex-specific liver growth in adult zebrafish, and together with MTOR, was required for full liver regrowth after injury. E2 produced increases in male liver weight that were significantly reduced in gper1–/– mutants. Exogenous E2 caused a 6-fold increase in gper1 expression in livers of male zebrafish, compared with livers of female fish. GPER1 was expressed at higher levels in human normal liver tissues from men than from women, consistent with the zebrafish analysis. Studies are needed to determine the mechanisms of increased GPER1 expression in male liver.

GPER1 appears to promote hepatocarcinogenesis; gper1–/– fish developed significantly fewer and smaller liver tumors than wild-type fish. Chaturantabut et al found human cirrhotic liver and hepatocellular carcinoma (HCC) tissues to have higher levels of GPER1 than normal liver tissues. Primary human hepatocytes incubated with E2 activated AKT1 signaling via MTOR and increased proliferation. An inhibitor of GPER1 in zebrafish reduced E2-induced liver tumor progression after chemical carcinogenesis, particularly in males.

The authors conclude that GPER1 is an essential component of the sexually dimorphic response to E2 during liver growth, including carcinogenesis. Previously, the E2 receptor antagonist tamoxifen was not found to increase survival times of patients with HCC in clinical trials. Tamoxifen and fulvestrant were subsequently found to be agonists for GPER1, which might account for the negative results of these agents in trials. Chaturantabut et al observed that fulvestrant induced phosphorylation of AKT and increased liver tumor burden in zebrafish.

Levels of E2 rapidly increase after liver resection in patients, pregnancy is associated with hepatomegaly, and gestational E2 promotes liver repair, indicating the physiologic benefits of E2 during periods of liver growth. Chaturantabut et al found that gper1–/– mutants had significantly delays in liver outgrowth during development and after injury. Nevertheless, gper1–/– mutants had a greater capacity for liver regeneration than mtor–/– mutants. The authors conclude that E2 signaling via GPER1 is only 1 pathway regulated by MTOR that regulates liver regeneration.

The findings are of particular importance because men with cirrhosis have persistent increases in serum levels of E2, and these patients are at highest risk for developing liver cancer. The ability of E2 signaling via GPER1 to activate MTOR and hepatocyte proliferation, and the effects of GPER1 antagonists on tumor growth and development in zebrafish, indicate that strategies to disrupt this pathway might be developed for treatment or prevention of liver cancer. GPER1 might also serve as a biomarker of liver tumor development.

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