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

Author:
Hartwell, Hadley J., Petrosky, Keiko Y., Fox, James G., Horseman, Nelson D., Rogers, Arlin B.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.31 pp. 11455-11460
ISSN:
0027-8424
Subject:
Toll-like receptor 4, animal models, antagonists, carcinogenesis, dopamine receptors, females, hepatitis B, hepatoma, hormone replacement therapy, humans, immune response, inflammation, innate immunity, interleukin-1beta, liver, males, men, mice, mitogen-activated protein kinase, mitogen-activated protein kinase kinase kinase, phenotype, postmenopause, prolactin, prolactin receptors, risk factors, sex hormones, transcription factor NF-kappa B, transgenic animals, tumor necrosis factor-alpha, viruses, women
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.
Agid:
1786796