Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours

Nat Commun. 2014 Dec 17;5:5809. doi: 10.1038/ncomms6809.

Abstract

Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting β-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of β-catenin. β-catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of β-catenin suppresses the tumorigenesis and growth of Men1-deficient PNETs, and significantly prolongs the survival time in mice. Suppression of β-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of β-catenin has no adverse effect on physiological function of pancreatic β-cells. Our data demonstrate that β-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Hyperinsulinism / pathology
  • Hypoglycemia / genetics
  • Hypoglycemia / metabolism
  • Hypoglycemia / pathology
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Endocrine Neoplasia Type 1 / genetics
  • Multiple Endocrine Neoplasia Type 1 / metabolism*
  • Multiple Endocrine Neoplasia Type 1 / mortality
  • Multiple Endocrine Neoplasia Type 1 / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Precision Medicine
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics*
  • Signal Transduction*
  • Survival Analysis
  • beta Catenin / deficiency
  • beta Catenin / genetics*

Substances

  • CTNNB1 protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • beta Catenin