Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice

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 repl...

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Bibliographic Details
Main Authors: Hartwell, Hadley J. (Author), Petrosky, Keiko Y. (Author), Fox, James G. (Contributor), Horseman, Nelson D. (Author), Rogers, Arlin B. (Author)
Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Division of Comparative Medicine (Contributor)
Format: Article
Language:English
Published: National Academy of Sciences (U.S.), 2015-03-04T15:55:33Z.
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Online Access:Get fulltext
LEADER 02818 am a22002413u 4500
001 95792
042 |a dc 
100 1 0 |a Hartwell, Hadley J.  |e author 
100 1 0 |a Massachusetts Institute of Technology. Department of Biological Engineering  |e contributor 
100 1 0 |a Massachusetts Institute of Technology. Division of Comparative Medicine  |e contributor 
100 1 0 |a Fox, James G.  |e contributor 
700 1 0 |a Petrosky, Keiko Y.  |e author 
700 1 0 |a Fox, James G.  |e author 
700 1 0 |a Horseman, Nelson D.  |e author 
700 1 0 |a Rogers, Arlin B.  |e author 
245 0 0 |a Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice 
260 |b National Academy of Sciences (U.S.),   |c 2015-03-04T15:55:33Z. 
856 |z Get fulltext  |u http://hdl.handle.net/1721.1/95792 
520 |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. 
520 |a National Institutes of Health (U.S.) (Grant CA067529) 
546 |a en_US 
655 7 |a Article 
773 |t Proceedings of the National Academy of Sciences of the United States of America