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

Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11455-60. doi: 10.1073/pnas.1404267111. Epub 2014 Jul 21.


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.

Keywords: innate immunity; lactotrophs; liver neoplasms; sex dimorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Carcinogenesis / pathology
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control*
  • Domperidone / pharmacology
  • Domperidone / therapeutic use
  • Female
  • Humans
  • Immunity, Innate* / drug effects
  • Inflammation / pathology
  • Interleukin-1beta / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control*
  • Male
  • Mice
  • Models, Biological
  • NF-kappa B / metabolism
  • Prolactin / deficiency
  • Prolactin / pharmacology
  • Prolactin / therapeutic use*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Prolactin / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • ras Proteins / metabolism


  • Interleukin-1beta
  • NF-kappa B
  • Proto-Oncogene Proteins c-myc
  • Receptors, Prolactin
  • TLR3 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Domperidone
  • Prolactin
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins

Associated data

  • GEO/GSE55669