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

Hormonally active women are better protected from the primary liver cancer hepatocellular carcinoma (HCC) than men. In rodent models, the pituitary gland governs sexually dimorphic HCC risk. We found that the estrogen-responsive pituitary hormone prolactin (PRL) inhibits HCC by binding liver short-form prolactin receptors, resulting in accelerated degradation of a multimolecular “trafasome” involved in tumor-promoting innate immune signaling and preventing activation of the HCC-associated gene c-Myc. Mouse models confirmed sex-dependent HCC regulation upstream of c-Myc and a requirement for PRL but not estrogen in female tumor resistance. Importantly, a preclinical trial in mice showed that pharmacologic PRL mobilization using the human drug domperidone protected males from HCC. PRL-targeted therapy may help prevent liver cancer in high-risk men and women.