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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (31), p.11455-11460
• Main Authors: Hartwell, Hadley J., Petrosky, Keiko Y., Fox, James G., Horseman, Nelson D., Rogers, Arlin B.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological Sciences; Carcinogenesis - pathology; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - prevention & control; Cell lines; Domperidone - pharmacology; Domperidone - therapeutic use; Female; Genes; Hepatitis B virus; Hepatocellular carcinoma; Hepatocytes; Hormones; Humans; Immune system; Immunity, Innate - drug effects; Inflammation - pathology; Interleukin-1beta - pharmacology; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Liver Neoplasms - prevention & control; Male; Men; Mice; Models, Biological; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Prolactin - deficiency; Prolactin - pharmacology; Prolactin - therapeutic use; Prolactin receptors; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - metabolism; ras Proteins - metabolism; Receptors, Prolactin - metabolism; Risk factors; Rodents; Signal Transduction - drug effects; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 4 - metabolism; Tumor Microenvironment - drug effects; Tumor Necrosis Factor-alpha - metabolism; Tumors; Women
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1404267111

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.