dc.contributor.author | Hartwell, Hadley J. | |
dc.contributor.author | Petrosky, Keiko Y. | |
dc.contributor.author | Fox, James G. | |
dc.contributor.author | Horseman, Nelson D. | |
dc.contributor.author | Rogers, Arlin B. | |
dc.date.accessioned | 2015-03-04T15:55:33Z | |
dc.date.available | 2015-03-04T15:55:33Z | |
dc.date.issued | 2014-07 | |
dc.date.submitted | 2014-03 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/95792 | |
dc.description.abstract | 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. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant CA067529) | en_US |
dc.language.iso | en_US | |
dc.publisher | National Academy of Sciences (U.S.) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1073/pnas.1404267111 | en_US |
dc.rights | Article 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.source | National Academy of Sciences (U.S.) | en_US |
dc.title | Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Hartwell, 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.department | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Division of Comparative Medicine | en_US |
dc.contributor.mitauthor | Fox, James G. | en_US |
dc.relation.journal | Proceedings of the National Academy of Sciences of the United States of America | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dspace.orderedauthors | Hartwell, Hadley J.; Petrosky, Keiko Y.; Fox, James G.; Horseman, Nelson D.; Rogers, Arlin B. | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9307-6116 | |
mit.license | PUBLISHER_POLICY | en_US |
mit.metadata.status | Complete | |