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

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.

The Sexually Dimorphic Adrenal Cortex: Implications for Adrenal Disease

“…Based on the aforementioned studies, the general pattern that emerges is that female mice are more prone to diseases of adrenocortical hyperactivity and tumorigenesis, while male mice are more prone to adrenocortical atrophy. However, not all adrenocortical tumor models display female bias: in a model of metastatic ACC induced by the combination of Trp53 deletion and β-catenin constitutive activation, no difference in the timing of tumor onset was observed between the sexes [ 48 ]. In another ACC model, due to Igf2 /H19 loss of imprinting and Apc deletion, hyperplasia is observed first in males [ 49 ].…”

Pan-Cancer Analysis of the Carcinogenic Effect of Nuclear Respiratory Factor-1 (NRF1) in Human Tumors

“…In the genetic analysis of ACC, "ampli cation" (2.2%, n=91) was the main mutation type, and the effect of this mutation on ACC and downstream proteins remains to be further studied. Studies have shown that activate Wnt/β-catenin and delete p53 synergically induce adrenal cortical carcinoma in mice [24], and studies have shown that NRF1 has inhibitory effect on Wnt/β-catenin signal transduction in mouse liver [25]. However, the role of NRF1 in regulating of Wnt/β-catenin activation and p53 in adrenal cortical carcinoma remains to be further studied.…”

How good are the current models of adrenocortical carcinoma for novel drug discovery?

“…This model has allowed to prove the efficacy of mTORC1 inhibition by rapamycin on tumor development. Recently, Borges et al developed another ACC mouse model with simultaneous β-catenin activation combined with Trp53 deletion and observed ACC development with metastases [9]. NCI-H295R xenografts have been established and solid tumors were locally measurable, however no development of metastasis was observed in those tumor-bearing mice.…”