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|a Hartwell, Hadley J.
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|a Massachusetts Institute of Technology. Department of Biological Engineering
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|a Massachusetts Institute of Technology. Division of Comparative Medicine
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|a Fox, James G.
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|a Petrosky, Keiko Y.
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|a Fox, James G.
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|a Horseman, Nelson D.
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|a Rogers, Arlin B.
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|a Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice
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|b National Academy of Sciences (U.S.),
|c 2015-03-04T15:55:33Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/95792
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|a Women are more resistant to hepatocellular carcinoma (HCC) than men despite equal exposure to major risk factors, such as hepatitis B or C virus infection. Female resistance is hormone-dependent, as evidenced by the sharp increase in HCC incidence in postmenopausal women who do not take hormone replacement therapy. In rodent models sex-dimorphic HCC phenotypes are pituitary-dependent, suggesting that sex hormones act via the gonadal-hypophyseal axis. We found that the estrogen-responsive pituitary hormone prolactin (PRL), signaling through hepatocyte-predominant short-form prolactin receptors (PRLR-S), constrained TNF receptor-associated factor (TRAF)-dependent innate immune responses invoked by IL-1β, TNF-α, and LPS/Toll-like receptor 4 (TLR4), but not TRIF-dependent poly(I:C)/TLR3. PRL ubiquitinated and accelerated poststimulatory decay of a "trafasome" comprised of IRAK1, TRAF6, and MAP3K proteins, abrogating downstream activation of c-Myc-interacting pathways, including PI3K/AKT, mTORC1, p38 MAPK, and NF-κB. Consistent with this finding, we documented exaggerated male liver responses to immune stimuli in mice and humans. Tumor promotion through, but regulation above, the level of c-Myc was demonstrated by sex-independent HCC eruption in Alb-Myc transgenic mice. PRL deficiency accelerated liver carcinogenesis in Prl[superscript −/−] mice of both sexes. Conversely, pharmacologic PRL mobilization using the dopamine D2 receptor antagonist domperidone prevented HCC in tumor-prone C3H/HeN males. Viewed together, our results demonstrate that PRL constrains tumor-promoting liver inflammation by inhibiting MAP3K-dependent activation of c-Myc at the level of the trafasome. PRL-targeted therapy may hold promise for reducing the burden of liver cancer in high-risk men and women.
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|a National Institutes of Health (U.S.) (Grant CA067529)
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|a en_US
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|a Article
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|t Proceedings of the National Academy of Sciences of the United States of America
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