Fig. 5.

Possible mechanisms of involvement of nuclear receptor LRH-1 in development of pancreatic cancer. Indicated are major transcriptional targets of LRH-1 and regulatory pathways mediated by the receptor. The expression of LRH-1 (yellow symbol) is controlled by the pancreas-specific master transcription factor PDX-1 (indicated in green) and via hedgehog signaling pathway that are both reactivated in pancreatic cancer. Activating mutations in the LRH-1 gene and its regulatory regions might contribute to the receptor up-regulation. The activated receptor functions synergistically with β-catenin (shown in purple), activating multiple target genes regulating cell growth and proliferation (Cyc D1, Cyc E1, and C-Myc, indicated in gray) as well as cell differentiation (Oct4, Nanog, indicated in gray). The cumulative effect of the aberrant, LRH-1 mediated activation of these multiple targets in adult pancreas results in tumorigenesis and metastasis.