Skin carcinogenesis in Ras/fos/PTEN^null transgenic mice associates reveals mTOR association with papillomatogenesis/conversion and AKT with malignant progression

MacDonald, F.H., Quinn, J.A. and Greenhalgh, D.A. (2011) Skin carcinogenesis in Ras/fos/PTEN^null transgenic mice associates reveals mTOR association with papillomatogenesis/conversion and AKT with malignant progression. British Journal of Dermatology, 164(4), p. 934. (doi: 10.1111/j.1365-2133.2011.10279.x)

Abstract

The conversion of benign tumour to malignancy depends on a complex combination of the genetic mutation milieu and the sentinel systems that resist carcinogenesis. In transgenic mouse skin carcinogenesis driven by <i>ras^Ha/fos</i> activation [<i>HK1.ras/fos</i>] and RU486-induced <i>PTEN</i> loss, we previously demonstrated that [<i>HK1.ras/fos-Δ5PTEN^flx</i> malignant conversion was delayed and progression limited to well-differentiated SSC histotypes [wdSCC]. This delay was associated with elevated p53/p21 expression until p53 was lost in late-stage papillomas, whereas p21 persisted and limit early-stage progression to wdSCCs. Given the regulation of AKT, and its target mTOR, by PTEN, we now determined their stage-specific expression profiles and found that, despite PTEN loss, expression of activated AKT [p-AKT] was low/absent in [<i>HK1.ras/fos-Δ5PTEN^flx</i> hyperplasia, papillomas and sporadic in wdSCCs. With time, p-AKT expression increased in p53 –negative wdSCCs and concomitant with this rise, punctate, nuclear p21 expression in basal layers became increasingly cytoplasmic, giving a peri-nuclear staining pattern. Hence early progression may involve an AKT-mediated exclusion of p21 from the nucleus, and once p-AKT expression became uniform in overt SCCs, p21 expression was undetectable. In being a major target of AKT activation, a similar profile was envisaged for m-TOR. However unlike p-AKT, p-mTOR was strongly expressed in [<i>HK1.ras/fos-Δ5PTEN^flx</i> hyperplasia, alongside strong p53/p21, persisted in p21 positive/p53 negative wdSCCs, but then faded on progression to aggressive SCCs, despite uniform p-AKT expression. These data suggest once p53 was lost, elevated [AKT-independent] p-mTOR expression cooperated with ras/fos in a converting role, whilst AKT expression exerts major effect in later progression via inhibition of p21.

• Item Type: Articles
• Additional Information: Conference paper abstract
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and Quinn, Dr Jean
• Authors: MacDonald, F.H., Quinn, J.A., and Greenhalgh, D.A.
• Subjects: R Medicine > RB Pathology; R Medicine > RL Dermatology; R Medicine > RZ Other systems of medicine
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: British Journal of Dermatology
• ISSN: 0007-0963
• ISSN (Online): 1365-2133

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
55465	1	Analysis of tumour progression via inducible PTEN, p53 or p21 knockout.	David Greenhalgh	British Skin Foundation (BSF)	3013	MVLS MED - DERMATOLOGY