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Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice.

Authors
  • Borges, Kleiton Silva1, 2, 3
  • Pignatti, Emanuele1, 2
  • Leng, Sining1, 4
  • Kariyawasam, Dulanjalee1, 2
  • Ruiz-Babot, Gerard1, 2
  • Ramalho, Fernando Silva5
  • Taketo, Makoto Mark6
  • Carlone, Diana L1, 2, 7
  • Breault, David T8, 9, 10
  • 1 Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 2 Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil. , (Brazil)
  • 4 Division of Medical Sciences, Harvard Medical School, Boston, MA, 02115, USA.
  • 5 Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil. , (Brazil)
  • 6 Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8506, Japan. , (Japan)
  • 7 Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
  • 8 Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA. [email protected]
  • 9 Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. [email protected]
  • 10 Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. [email protected]
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jul 01, 2020
Volume
39
Issue
30
Pages
5282–5291
Identifiers
DOI: 10.1038/s41388-020-1358-5
PMID: 32561853
Source
Medline
Language
English
License
Unknown

Abstract

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS)Cre mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.

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