Genetic analysis of the cooperative tumorigenic effects of targeted deletions of tumor suppressors , , , and in neuroendocrine tumors in mice. Author Eugenia Xu, Evan Vosburgh, Chung Wong, Laura Tang, Daniel Notterman Publication Year 2020 Type Journal Article Abstract Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs , , and have cooperative effects in suppressing neuroendocrine tumors (NETs) in mice. We generated pairwise homozygous deletions of these four genes in insulin II gene expressing cells using the Cre-LoxP system. By monitoring growth and examining the histopathology of the pituitary (Pit) and pancreas (Pan) in these mice, we demonstrated that pRB had the strongest cooperative function with PTEN in suppressing PitNETs and had strong cooperative function with Menin and TRP53, respectively, in suppressing PitNETs and PanNETs. TRP53 had weak cooperative function with PTEN in suppressing pituitary lesions. We also found that deletion of singly led to prolactinomas in female mice, and deletion of alone led to islet hyperplasia in pancreas. Collectively, our data indicated that pRB and PTEN pathways play significant roles in suppressing PitNETs, while the Menin-mediated pathway plays a significant role in suppressing PanNETs. Understanding the molecular mechanisms of these genes and pathways on NETs will help us understand the molecular mechanisms of neuroendocrine tumorigenesis and develop effective preclinical murine models for NET therapeutics to improve clinical outcomes in humans. Journal Oncotarget Volume 11 Issue 28 Pages 2718-2739 Date Published 2020 Jul 14 ISSN Number 1949-2553 DOI 10.18632/oncotarget.27660 Alternate Journal Oncotarget PMCID PMC7367653 PMID 32733644 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML