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

Author(s)

Borges, Kleiton Silva ^{[1, 2, 3]} ; Pignatti, Emanuele ^{[1, 3, 4]} ; Leng, Sining ^{[1, 4, 5]} ; Kariyawasam, Dulanjalee ^{[1, 3, 4]} ; Ruiz-Babot, Gerard ^{[1, 3, 4]} ; Ramalho, Fernando Silva ^[6] ; Taketo, Makoto Mark ^[7] ; Carlone, Diana L. ^{[1, 3, 8, 4]} ; Breault, David T. ^{[1, 3, 8, 4]}

Affiliation

^[1] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 - USA

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Ribeirao Preto - Brazil

^[3] Harvard Med Sch, Dept Pediat, Boston, MA 02115 - USA

^[4] Breault, David T., Harvard Stem Cell Inst, Cambridge, MA 02138 USA.Borges, Kleiton Silva, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 - USA

^[5] Harvard Med Sch, Div Med Sci, Boston, MA 02115 - USA

^[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Ribeirao Preto - Brazil

^[7] Kyoto Univ, Grad Sch Med, Div Expt Therapeut, Kyoto 6068506 - Japan

^[8] Harvard Stem Cell Inst, Cambridge, MA 02138 - USA

• Document type: Journal article
• Source: Oncogene; v. 39, n. 30 JUN 2020.
• Web of Science Citations: 0

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/beta-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized theCyp11b2(AS)(Cre)mouse line to generate mice with adrenocortical-specific Wnt/beta-catenin activation,Trp53deletion, or the combination of both. Mice with targeted Wnt/beta-catenin activation orTrp53deletion 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 ofStarandCyp11b1and upregulation ofEzh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/beta-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. (AU)

• FAPESP's process: 16/00862-0 - To investigate the role of TP53 in adrenocortical zonation through targeted disruption in Aldosterone Synthase (AS)-expressing adrenal cells during post-natal development, maintenance and regeneration
• Grantee: Kleiton Silva Borges
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor