Transgenic Epidermal 14-3-3σ/stratifin Overexpression Cooperates with Pten Ablation to Give a Limited Carcinoma In Situ Phenotype

McMenemy, C. and Greenhalgh, D. A. (2022) Transgenic Epidermal 14-3-3σ/stratifin Overexpression Cooperates with Pten Ablation to Give a Limited Carcinoma In Situ Phenotype. British Journal of Dermatology 187(1):e21. Meeting Abstract: British Society for Investigative Dermatology Virtual Annual Meeting, 29–31 March 2021. (doi: 10.1111/bjd.20477)

Abstract

PTEN is a major tumour suppressor gene that negatively regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. The phenotypes associated with PTEN mutation are dose dependent, i.e. mutant allele heterozygosity (PTEN+/–) results in a less severe phenotype than full ablation (PTEN–/–). In the skin, loss of PTEN results in Cowden disease, which has been recapitulated in mice by ablation of exon 5, which encodes the core catalytic motif responsible for inhibition of AKT activation. This was achieved using an inducible Cre-loxP system driven by a K14 promoter, generating a Ptenflx/flx genotype, which resulted in mild hyperplasia, dysplasia and hyperkeratosis. These mice also develop a noticeably ‘woolly’ appearance to the fur, likely due to impaired follicle development. However, alone, the K14.cre/Ptenflx/flx genotype did not result in overt neoplasia for over 12 months. Another important molecule in the epidermis is 14-3-3σ/stratifin, an adapter protein named for its importance in the development of stratified epithelia. Among the many functions of the 14-3-3 superfamily, stratifin is associated with keratinocyte spatial awareness; roles in epidermal differentiation and proliferation; and is well known to be induced by elevated p53 levels following DNA damage, thus inhibiting Mdm2 in a positive feedback loop. 14-3-3σ/stratifin has been shown to possess tumour-suppressive functions such as direct inhibition of oncogenic AKT activities, hence the study with PTEN. Conversely, studies of human carcinomas have found elevated 14-3-3σ/stratifin in malignant squamous cell carcinoma relative to normal adjacent tissues, thereby suggesting possible oncogenic activity. Supporting this idea previously, in conjunction with overexpression of oncogenes Fos and H-Ras, overexpression of stratifin via a K14 promoter (K14.stratifin) resulted in novel carcinomas with several distinctive features – some suggesting a follicular origin. Given this latter observation, here K14.stratifin was expressed concurrently with partial (Ptenwt/flx) and full (Ptenflx/flx) Pten ablation. Preliminary results showed that the gross and histological phenotypes of the K14.stratifin/Ptenflx/flx mice were exacerbated by elevated stratifin expression. While the severity of the induced phenotype differed slightly between mice, histological analysis suggests that carcinoma in situ frequently developed, with evidence of local invasion. These initial results suggest that, as in previously demonstrated models, overexpression of epidermal stratifin results in oncogenic activity rather than rescue of the Cowden phenotype.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and MCMENEMY, Carol
• Authors: McMenemy, C., and Greenhalgh, D. A.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• ISSN: 0007-0963
• Published Online: 03 July 2022