title: RB tumor suppressive function in response to xenobiotic hepatocarcinogens.
abstract: Diverse etiologic events are associated with the development of hepatocellular carcinoma. During hepatocarcinogenesis, genetic events likely occur that subsequently cooperate with long-term exposures to further drive the progression of hepatocellular carcinoma. In this study, the frequent loss of the retinoblastoma (RB) tumor suppressor in hepatocellular carcinoma was modeled in response to diverse hepatic stresses. Loss of RB did not significantly affect the response to a steatotic stress as driven by a methionine- and choline-deficient diet. In addition, RB status did not significantly influence the response to peroxisome proliferators that can drive hepatomegaly and tumor development in rodents. However, RB loss exhibited a highly significant effect on the response to the xenobiotic1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene. Loss of RB yielded a unique proliferative response to this agent, which was distinct from both regenerative stresses and genotoxic carcinogens. Long-term exposure to 1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene yielded profound tumor development in RB-deficient livers that was principally absent in RB-sufficient tissue. These data demonstrate the context specificity of RB and the key role RB plays in the suppression of hepatocellular carcinoma driven by xenobiotic stress.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Christopher
authors.initials: C
authors.lastname: Reed
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Mayhew
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: erik.knudsen@utsouthwestern.edu.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008817:Mice, Mutant Strains; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015262:Xenobiotics / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D011725:Pyridines; D016160:Retinoblastoma Protein; D015262:Xenobiotics; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene
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