Skin carcinogenesis in Ras/fos/PTENnull 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/PTENnull 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)

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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<sup>Ha</sup>/fos</i> activation [<i>HK1.ras/fos</i>] and RU486-induced <i>PTEN</i> loss, we previously demonstrated that [<i>HK1.ras/fos-Δ5PTEN<sup>flx</sup></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<sup>flx</sup></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<sup>flx</sup></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
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 > Institute of Infection Immunity and Inflammation
Journal Name:British Journal of Dermatology
ISSN (Online):1365-2133

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
554651Analysis of tumour progression via inducible PTEN, p53 or p21 knockout.David GreenhalghBritish Skin Foundation (BSF)3013MVLS MED - DERMATOLOGY