Clinically Defined Mutations in MEN1 Alter Its Tumor-suppressive Function Through Increased Menin Turnover

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Loss of the tumor suppressor protein menin is crucial in neuroendocrine tumor (NET) development.
• Clinical mutations in the multiple endocrine neoplasia type 1 (MEN1) gene are linked to NETs, but their precise impact on menin stability and function requires further investigation.

Purpose of the Study:

• To determine if clinical MEN1 mutations destabilize nuclear menin, leading to functional inactivation.
• To assess the therapeutic potential of the small-molecule compound MI-503 in restoring menin function and treating MEN1-associated NETs.

Main Methods:

• Studied the structural and functional implications of MEN1 mutations (R516fs, E235K) and a variant (A541T).
• Evaluated menin mutant localization, half-lives, and function (cell proliferation, gastrin expression) in cell lines and mouse models.
• Assessed the effect of MI-503 on menin expression and NET development in mice.

Main Results:

• MEN1 mutants R516fs and E235K showed reduced menin expression and half-lives, leading to loss of tumor suppressor function.
• Mutated menin failed to suppress cell proliferation and gastrin expression.
• MI-503 treatment restored nuclear menin, reduced hypergastrinemia, and attenuated gastric hyperplasia in mice.

Conclusions:

• Clinically defined MEN1 mutations and germline variants confer pathogenicity by destabilizing nuclear menin.
• MI-503 effectively restores menin protein expression and function, representing a promising therapeutic strategy for MEN1-associated gastroenteropancreatic NETs.