HOX genes promote cell proliferation and are potential therapeutic targets in adrenocortical tumours

Jeffrey C Francis,Pierre Val,Celso Gomez-Sanchez,Yacob Weinstein,Yoan Renaud,Jennifer R Gardiner,Anne-Marie Lefrançois-Martinez,Jérôme Bertherat,Amanda Swain,Ritika Chauhan

doi:10.1038/s41416-020-01166-z

Abstract

BackgroundUnderstanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment.MethodsWe used transgenic mouse models to determine the role of Hoxb9 in adrenal tumour development. Patient transcriptomic data was analysed for the expression of HOX genes and their association with disease. Drug response studies on various adrenocortical models were done to establish novel therapeutic options.ResultsOur human ACC dataset analyses showed high expression of HOXB9, and other HOX factors, are associated with poorer prognosis. Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours. This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne1. Adrenal tumour cells were found to be dependent on HOX function for survival and were sensitive to a specific peptide inhibitor.ConclusionsThese studies show Hoxb9 can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC.

Highlights

Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies
To investigate if HOXB9 expression is associated with ACC, we analysed patient gene expression data from the Cochin cohort that contains normal adrenal (NAd), adrenocortical adenoma (ACA) and ACC samples.[3]
Consistent with HOXB9 expression being associated with aggressive disease, analyses of The Cancer Gene Atlas (TCGA) and Cochin patients into high and low HOXB9 expression showed that ACC patients with high HOXB9 expression had a poorer survival prognosis (Fig. 1c)

Summary

Introduction

Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. Transgenic overexpression of Hoxb[9] in the adrenal cortex of mice with activated Ctnnb[1] led to larger adrenal tumours This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne[1]. CONCLUSIONS: These studies show Hoxb[9] can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC. Tumours of the adrenal cortex are relatively common with a prevalence of 1–10% Most of these are benign adenomas, in rare cases (up to 2 per million per year) adrenocortical carcinoma (ACC) can develop, which is an aggressive disease with a low 5-year survival (up to 35% of diagnosed patients and less than 15% in patients with metastatic disease) Recent next-generation sequencing studies have revealed recurrent alterations present in patients with ACC.[3,4,5] These studies have identified mutations in the WNT signalling pathway to be one of the most frequent alterations, with CTNNB1-activating mutations present in up to 16% and inactivating changes in ZNRF3, a pathway repressor, in up to 21%.3 Other pathways that are altered in ACC patients include epigenetic regulation and p53/RB1 and PKA signalling.[5]

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Conclusion