title: Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice.
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(-/-) 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.
authors: Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors: Hadley J
authors: HJ
authors: Hartwell
authors: Division of Comparative Pathology, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772;
authors: Keiko Y
authors: KY
authors: Petrosky
authors: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors: James G
authors: JG
authors: Fox
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45267.
authors: Nelson D
authors: ND
authors: Horseman
authors: Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536; Arlin.Rogers@tufts.edu.
authors: Arlin B
authors: AB
authors: Rogers
mesh_terms: D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004294:Domperidone / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011388:Prolactin / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011981:Receptors, Prolactin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D011981:Receptors, Prolactin; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D004294:Domperidone; D011388:Prolactin; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: innate immunity; lactotrophs; liver neoplasms; sex dimorphism