Abstract
Simple SummaryThe hormone estrogen is well known for its role in promoting breast and ovarian cancer. Estrogen has the opposite effect on the liver, which it protects from cancer. We show that this protection requires Estrogen Receptor α, but not Estrogen Receptor β, and correlates with a female pattern of liver gene expression. Female expression in the liver requires Estrogen Receptor α expressed in non-liver cells. Surgical removal of the ovaries, which protect females from liver cancer at least in part through their production of estrogen, does not affect the female-specific liver gene expression pattern. Estrogen may therefore influence liver carcinogenesis through multiple independent mechanisms. We identify six genes that are strong candidates for mediating Esr1′s protection against liver cancer.Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.
Highlights
Liver cancer is the second leading cause of cancer death worldwide [1]
To determine whether Esr1 influences hepatocellular carcinoma (HCC) development, female Esr1 KO, Esr1 heterozygous, and WT littermates were treated with 0.1 μmol/g body weight DEN at 12 days of age and euthanized at 50 weeks. (This dose of DEN was chosen based on previous experiments analyzing the effect of sex hormones on hepatocarcinogenesis [16].) Analyses of liver tumor multiplicity and incidence (Table 1) show that Esr1 has a strong protective effect
We found that Esr1 dramatically protects female mice from liver tumor development
Summary
Men are twice as likely as women to develop liver cancer and to die from it [1,2]. The female hormone estrogen is well known as a cancer promoter in tissues such as the breast, endometrium, and ovary; but in the liver, estrogen is protective [3,4,5,6]. Epidemiological evidence suggests that liver cancer incidence is increased in postmenopausal females, that estrogen treatment suppresses liver cancer, and that the number of full-term pregnancies affects susceptibility to liver cancer [3,4,5]. In clinical trials, treating HCC patients with tamoxifen, which binds. Estrogen Receptor α and blocks the effect of estrogen, resulted in a dose-dependent detrimental response with significantly fewer patients surviving for three months at higher doses [7]. The mechanism of estrogen’s protection is not well understood [3]
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