Constitutive β-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development

Adrenocortical carcinoma is a rare but aggressive cancer with unknown aetiology. Constitutive activation of β-catenin is the most frequent alteration in benign and malignant adrenocortical tumours in patients. Here, we show that constitutive activation of β-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cells hyperplasia as well as dysplasia of the cortex and medulla. Over a 17 months time course, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Altogether these observations demonstrate that constitutively active β-catenin is an adrenal oncogene which triggers benign aidosterone-secreting tumour development and promotes malignancy.