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Wnt/ß-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice.
Borges, Kleiton Silva; Pignatti, Emanuele; Leng, Sining; Kariyawasam, Dulanjalee; Ruiz-Babot, Gerard; Ramalho, Fernando Silva; Taketo, Makoto Mark; Carlone, Diana L; Breault, David T.
Afiliación
  • Borges KS; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Pignatti E; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
  • Leng S; Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
  • Kariyawasam D; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Ruiz-Babot G; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
  • Ramalho FS; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Taketo MM; Division of Medical Sciences, Harvard Medical School, Boston, MA, 02115, USA.
  • Carlone DL; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Breault DT; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
Oncogene ; 39(30): 5282-5291, 2020 07.
Article en En | MEDLINE | ID: mdl-32561853
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/ß-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/ß-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/ß-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/ß-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Neoplasias de la Corteza Suprarrenal / Modelos Animales de Enfermedad / Beta Catenina / Vía de Señalización Wnt Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Neoplasias de la Corteza Suprarrenal / Modelos Animales de Enfermedad / Beta Catenina / Vía de Señalización Wnt Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido