Inducible ß-Catenin Activation and PTEN Inactivation Elicit Follicular Tumours, Not Papillomas: A Potential Paradigm for Trichilemmomas in Cowden’s Disease

Tan, J., Mészáros, J., Young, L. and Greenhalgh, D. A. (2017) Inducible ß-Catenin Activation and PTEN Inactivation Elicit Follicular Tumours, Not Papillomas: A Potential Paradigm for Trichilemmomas in Cowden’s Disease. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

Tan, J., Mészáros, J., Young, L. and Greenhalgh, D. A. (2017) Inducible ß-Catenin Activation and PTEN Inactivation Elicit Follicular Tumours, Not Papillomas: A Potential Paradigm for Trichilemmomas in Cowden’s Disease. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

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Abstract

β-catenin is a dual-function protein established as a key downstream effector in the Wnt signalling pathway and may become oncogenic when dysregulated. Previous studies have suggested that failure in β-catenin signalling regulation via GSK3β inactivation may be involved in transgenic mouse skin carcinogenesis driven by Ras/Fos activation and inducible PTEN inactivation. In this model, bi-genic HK1.fos-5PTENflx demonstrated increasing GSK3β inactivation triggered compensatory p53/p21 responses presumably to nuclear accumulation of activated β-catenin, and which prevented malignant conversion. In tri-genic HK1.fos/ras/5PTEN mice, such p-GSK3βser9 inactivation was associated with increased nuclear/decreased membranous β-catenin following malignant conversion. Here stabilised Δ3β-catenin was expressed alongside inducible PTEN ablation employing topical application of RU-486 [mifepristone]. Intriguingly, despite a significant increased in interfollicular hyperplasia, no K14.creP-Δ3β-cat/Δ5PTEN mice developed papillomas; nor SCC. Instead, mice displayed increased follicular hyperplasia compared to β-catenin activation or PTEN inactivation alone; together with numerous cysts and sebaceous gland hyperplasia; resulting in greasy fur. Interestingly the follicular histopathology observed in treated Δ3β-cat/Δ5PTEN was deemed similar to that of Multiple Trichilemmomas, a hair follicle tumour often seen in Cowden’s Disease. Analysis of p53 and p21 showed an increased p21 expression response that may inhibit/antagonise Δ5PTEN-mediated AKT activation; as p-AKT1 expression was weak and p-AKT2 expression was absent. Expression of keratin K15, a stem cells marker, was also reduced, suggesting that β-catenin activation may deplete the stem cell populations required for papilloma aetiology and this facet in combination with increased p21 and reduced AKT, may explain the lack of typical papillomas. In contrast, increased fatty acid synthase expression was seen, consistent with the development of sebomas over time. As the origin of Multiple Trichilemmomas is unknown in Cowden’s Disease, this co-operation between PTEN and β-catenin provides a logical potential mechanism driving the aetiology of this tumour type and an insight to the mechanisms underlying this novel co-operation between deregulated β-catenin and PTEN signalling.

Item Type:Conference or Workshop Item
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Greenhalgh, Dr David
Authors: Tan, J., Mészáros, J., Young, L., and Greenhalgh, D. A.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
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