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dc.contributor.authorHartwell, Hadley J.
dc.contributor.authorPetrosky, Keiko Y.
dc.contributor.authorFox, James G.
dc.contributor.authorHorseman, Nelson D.
dc.contributor.authorRogers, Arlin B.
dc.date.accessioned2015-03-04T15:55:33Z
dc.date.available2015-03-04T15:55:33Z
dc.date.issued2014-07
dc.date.submitted2014-03
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/95792
dc.description.abstractWomen 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.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant CA067529)en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1404267111en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceNational Academy of Sciences (U.S.)en_US
dc.titleProlactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in miceen_US
dc.typeArticleen_US
dc.identifier.citationHartwell, H. J., K. Y. Petrosky, J. G. Fox, N. D. Horseman, and A. B. Rogers. “Prolactin Prevents Hepatocellular Carcinoma by Restricting Innate Immune Activation of c-Myc in Mice.” Proceedings of the National Academy of Sciences 111, no. 31 (July 21, 2014): 11455–11460.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Division of Comparative Medicineen_US
dc.contributor.mitauthorFox, James G.en_US
dc.relation.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsHartwell, Hadley J.; Petrosky, Keiko Y.; Fox, James G.; Horseman, Nelson D.; Rogers, Arlin B.en_US
dc.identifier.orcidhttps://orcid.org/0000-0001-9307-6116
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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