Genetic analysis of the cooperative tumorigenic effects of targeted deletions of tumor suppressors Rb1, Trp53, Men1, and Pten in neuroendocrine tumors in mice

TitleGenetic analysis of the cooperative tumorigenic effects of targeted deletions of tumor suppressors Rb1, Trp53, Men1, and Pten in neuroendocrine tumors in mice
Publication TypeJournal Article
Year of Publication2020
AuthorsXu, EY, Vosburgh, E, Wong, C, Tang, LH, Notterman, DA
JournalOncotarget
Volume11
Issue28
Pagination2718-2739
Date Published2020 Jul 14
ISSN1949-2553
Abstract

Genetic alterations of tumor suppressor genes (TSGs) are frequently observed to have cumulative or cooperative tumorigenic effects. We examined whether the TSGs Rb1, Trp53, Pten and Men1 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 Pten singly led to prolactinomas in female mice, and deletion of Rb1 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.

DOI10.18632/oncotarget.27660
Alternate JournalOncotarget
PubMed ID32733644
PubMed Central IDPMC7367653