title: Trp53 inactivation leads to earlier phaeochromocytoma formation in pten knockout mice.
abstract: Phaeochromocytomas (PCCs) are benign neuroendocrine tumours of the adrenal medulla. Approximately 10% of PCC patients develop metastases, but this frequency is much higher in specific subtypes of patients. The reliable diagnosis of malignant PCC can only be made after identification of a metastasis. To study the effect of Trp53 inactivation on PCC pathogenesis in Pten KO mice, we investigated the adrenals of a large cohort of mice with conditional monoallelic and biallelic inactivation of Trp53 and Pten. The adrenal weights were determined for all mice, and in a proportion of these mice, immunohistochemistry for tyrosine hydroxylase and dopamine β-hydroxylase was performed on the adrenals and corresponding lungs. Finally, comparative genomic hybridization (CGH) was performed. The histological and immunohistochemical results confirmed that the adrenal tumours were PCCs. Inactivation of one or both alleles of Trp53 resulted in earlier tumour occurrence in the Pten(loxP/loxP) mice as well as in the Pten(loxP/+) mice. In addition, lung metastases were found in up to 67% of mice. The CGH results showed that the most frequent genomic alterations were loss of chromosome 19 (86%) and gain of chromosome 15 (71%). In this study, we have shown that Pten/Trp53 KO mice showed metastatic PCC at high frequency and primary tumours occurred at younger ages in mice with Trp53 inactivation. Therefore, the present model appears to be a suitable model that might allow the preclinical study of new therapeutics for these tumours.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, CA Rotterdam, The Netherlands. e.korpershoek.1@erasmusmc.nl
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Nanne K
authors.initials: NK
authors.lastname: Kloosterhof
authors.forename: Angelique
authors.initials: A
authors.lastname: Ziel-van der Made
authors.forename: Hanneke
authors.initials: H
authors.lastname: Korsten
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: Jan
authors.initials: J
authors.lastname: Trapman
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000311:Adrenal Glands / Q000201:enzymology / Q000473:pathology; D000818:Animals; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010673:Pheochromocytoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse