title: Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.
abstract: 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.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Weyandt
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Lampson
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Sherry
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mastrodomenico
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cardona
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Counter
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)