Open AccessWild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
Author(s) -
Jamie D. Weyandt,
Benjamin L. Lampson,
Sherry Tang,
Matthew Mastrodomenico,
Diana M. Cardona,
Christopher M. Counter
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0140253
Subject(s) - hras , kras , neuroblastoma ras viral oncogene homolog , pancreatic cancer , carcinogenesis , cancer research , biology , cancer , context (archaeology) , wild type , adenocarcinoma , tumor initiation , mutant , genetics , colorectal cancer , gene , paleontology
Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras , which can be activated in the presence of oncogenic Kras . The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of Hras increases tumor load and reduces survival in an oncogenic Kras -driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type Hras may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of Hras are nullified in a homozygous mutant p53 background. As such, loss of wild-type Hras fosters the earliest stages of pancreatic cancer in a p53-dependent manner.