title: Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice.
abstract: Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mingjian James
authors.initials: MJ
authors.lastname: You
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Rónán C
authors.initials: RC
authors.lastname: O'Hagan
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000517:prevention & control; D009693:Nucleic Acid Hybridization; D051059:PTEN Phosphohydrolase; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human