Jeffrey C Francis1, Jennifer R Gardiner1, Yoan Renaud2, Ritika Chauhan3, Yacob Weinstein4, Celso Gomez-Sanchez5, Anne-Marie Lefrançois-Martinez2, Jérôme Bertherat6, Pierre Val2, Amanda Swain7. 1. Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK. 2. Genétique Reproduction & Développement, CNRS UMR 6293, Inserm U1103, Université Clermont Auvergne, 63001, Clermont-Ferrand, France. 3. Tumour Profiling Unit, The Institute of Cancer Research, 237 Fulham Road, London, UK. 4. The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel. 5. Division of Endocrinology, Medical Service, G.V. (Sonny) Montgomery VA Medical Center, 1500 E. Woodrow Wilson Dr, Jackson, MS, 39216, USA. 6. Institut Cochin, Inserm U1016, CNRS UMR 8104, Université Paris Descartes, UMR-S1016, 75014, Paris, France. 7. Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK. amanda.swain@icr.ac.uk.
Abstract
BACKGROUND: Understanding 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. METHODS: We 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. RESULTS: Our 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. CONCLUSIONS: These 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.
BACKGROUND: Understanding 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. METHODS: We used transgenicmouse 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. RESULTS: Our 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. CONCLUSIONS: These 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.
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