Editors' ChoiceCancer

Estrogen Represses Liver Tumors

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Science Signaling  04 Dec 2012:
Vol. 5, Issue 253, pp. ec308
DOI: 10.1126/scisignal.2003834

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death and occurs as much as five times more often in men than in women. As with other cancers, the presence in the HCC tumor microenvironment of alternatively activated tumor-associated macrophages (TAMs) is an indicator of poor prognosis. In contrast to conventionally activated macrophages, which secrete proinflammatory cytokines and kill tumor cells, alternatively activated TAMs are anti-inflammatory, are proangiogenic, and promote tumor growth. Given the gender bias in HCC incidence, Yang et al. investigated roles for androgens (male sex hormones) and estrogens (female sex hormones) in mouse xenograft models of human HCC. They found that liver tumor growth in ovariectomized (OVX) female mice was increased compared with that in control female mice and that the addition of 17β-estradiol (E2) reduced tumor growth in the OVX mice. In contrast, there was no difference in liver tumor size between control and castrated male mice; however, E2 reduced tumor size in the castrated mice. Immunofluorescence staining revealed that E2 treatment reduced the numbers of TAMs in the liver tumors of OVX and castrated mice compared with those in untreated mice. In vitro studies showed that E2 suppressed the interleukin-4 (IL-4)–dependent production of anti-inflammatory cytokines by a mouse macrophage cell line (ANA-1 cells); IL-4 activates TAMs in vivo. Western blotting and gene expression analyses showed that treatment of ANA-1 cells with E2 blocked IL-4–dependent signaling and target gene expression, and studies with selective estrogen receptor (ER) agonists showed that the inhibitory effects of E2 were mediated by ERβ but not ERα. Finally, Western blotting analysis showed that E2 disrupted the IL-4–dependent association of ERβ with a mitochondrial-associated adenosine triphosphatase, an association that is required for TAM activation. Together, these data show that estrogens suppress TAM activation to inhibit HCC growth and suggest that estrogen therapy may be effective in treating HCC in males.

W. Yang, Y. Lu, Y. Xu, L. Xu, W. Zheng, Y. Wu, L. Li, P. Shen, Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J. Biol. Chem. 287, 40140–40149 (2012). [Abstract] [Full Text]

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