Correlation between serum prolactin levels and hepatocellular tumorigenesis induced by 3'-methyl-4-dimethylaminoazobenzene in mice

Yamamoto, Reiko; Tatsuta, Masaharu; Yamamoto, Takashi; Koike, Koji; Kanda, Yuki; Miyake, Akira; Tsuji, Motomu; Terada, Nobuyuki

doi:10.1038/bjc.1995.270

Cited by 13 publications

(9 citation statements)

References 33 publications

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“…Nevertheless, our model reconciles previously disconnected rodent studies, and introduces a mechanism by which an E2-responsive pituitary hormone may help prevent HCC. Our results confirm and extend reports from other groups showing reduced HCC in mice and rats with PRL mobilization via pituitary allograft or pharmacologic induction (36,37). However, another study reported no impact of PRL receptor deficiency on DEN-initiated liver carcinogenesis in Prlr −/− mice (42).…”

Section: Discussionsupporting

confidence: 82%

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

Hartwell

Petrosky

Fox

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 gonadalhypophyseal 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.liver neoplasms | lactotrophs | innate immunity | sex dimorphism

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Section: Discussionsupporting

confidence: 82%

“…5E). Combined with studies elsewhere involving the PRL-mobilizing agents perphenazine and cimetidine (36,37), our results establish E2-independent PRL induction as a rational strategy to prevent HCC. …”

Section: Significancementioning

confidence: 79%

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

Hartwell

Petrosky

Fox

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The lesser susceptibility of women to HCC can also result from estrogen stimulated secretion of prolactin, another pituitary-secreted hormone 10,11 . In this context, prolactin may protect females from liver tumorigenesis by restricting innate immunity signaling in hepatocytes, which may be of special relevance for the virally-associated forms of the disease 10 In many cases, higher estrogen signaling, leading to ERβ activation, has been implicated as the likely explanation.…”

Section: Sex Hormone Signaling In Specific Cancer Typesmentioning

confidence: 99%

Sexual dimorphism in cancer

et al. 2016

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The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

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“…In subsequent experiments, evidence suggested that estradiol might be acting via its ability to stimulate prolactin production by the pituitary gland. In chemically‐treated mice that had been ovariectomized, implantation of pituitary glands led to increased levels of prolactin and reduction in the number of preneoplastic foci . There is also evidence that after diethylnitrosamine‐induction of liver tumors, inflammatory signalling, primarily interleukin‐6 (IL‐6) expression, is reduced by estrogens .…”

Section: Discussionmentioning

confidence: 81%

Menopausal hormone therapy use and risk of primary liver cancer in the clinical practice research datalink

et al. 2015

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Primary liver cancer occurs less commonly among women than men in almost all countries. This discrepancy has suggested that hormone levels and/or exogenous hormone use could have an effect on risk, although prior studies have reached inconsistent conclusions. Thus, the current study was conducted to examine the relationship between menopausal hormone therapy (MHT) use and development of liver cancer. A nested case-control study was conducted within the United Kingdom’s Clinical Practice Research Datalink (CPRD). Controls were matched, at a 4-to-1 ratio, to women diagnosed with primary liver cancer between 1988 and 2011. A second match, based on whether the cases and controls had diabetes, was also conducted. Odds ratios (OR) and 95% confidence intervals (95%CI) for associations of MHT with liver cancer were estimated using conditional logistic regression adjusted for known risk factors. In the overall match, 339 women with liver cancer were matched to 1318 controls. MHT use was associated with a significantly lower risk of liver cancer (ORadj=0.58, 95%CI=0.37–0.90) especially among users of estrogen-only MHT (ORadj=0.44, 95%CI=0.22–0.88) and among past users (ORadj=0.53, 95%CI=0.32–0.88). Among the matched cases (n=58) and controls (n=232) with diabetes, the odds ratios were similar to the overall analysis (ORadj=0.57, 95%CI=0.09–3.53), but did not attain statistical significance. In the current study, MHT use, especially estrogen-only MHT use, was associated with a significantly lower risk of liver cancer. These results support the need of further investigation into whether hormonal etiologies can explain the variation in liver cancer incidence between men and women.

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Correlation between serum prolactin levels and hepatocellular tumorigenesis induced by 3'-methyl-4-dimethylaminoazobenzene in mice

Cited by 13 publications

References 33 publications

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

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

Sexual dimorphism in cancer

Menopausal hormone therapy use and risk of primary liver cancer in the clinical practice research datalink

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