Alternative Pathways of Akt Pathway Activation in HPV Positive and Negative Penile Carcinomas.
Elzbieta Stankiewicz, David Mesher, Mansum Ng, Jack Cuzick, David Prowse, Frances Hiscock, Yong-Jie Lu, Wayne Lam, Nicholas Watkin, Cathy Corbishley, Daniel M Berney. Barts and The London School of Medicine, Queen Mary, University of London, United Kingdom; St George's Hospital, London, United Kingdom
Background: The pathogenesis of penile cancer (PC) is not well understood, and although risk factors include human papillomavirus (HPV) the pathogenesis of HPV negative cancers is not understood. Disruption of the HER/PTEN/Akt pathway is present in many cancers, however, there is little information on its function in PC. Therefore, we investigated the status of HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PC and its impact on Akt activation, using fluorescent in situ hybridisation (FISH) and immunohistochemistry to examine differences in HPV positive and negative carcinomas.
Design: 148 PCs from St George's Hospital were tissue microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt) and Akt1 proteins. Immunostains were assesed semi-quantitatively. EGFR and PTEN gene status was also evaluated using the FISH probes LSI EGFR (7p12)/CEP 7 Dual Color Probe and the LSI PTEN (10q23) / CEP 10 Dual Color Probe. FISH slides were scanned and a minimum of 100 cells with clear hybridization signals were counted per tumour core. HPV presence was assessed by a broad-spectrum HPV PCR method using SPF10 primers.
Results: pEGFR protein expression was positive in 25% of patients and significantly correlated with activated Akt (p<0.0001). There was no EGFR gene amplification. HER2 was not detected. HER3 (p=0.0054) and HER4 (p=0.0002) receptors significantly correlated with cytoplasmic Akt1 expression. All three proteins positively correlated with tumour grade (HER3, p=0.0029; HER4, p=0.01118; Akt1, p=0.0001). PTEN protein expression was reduced or absent in 62% of tumours. PTEN gene copy loss was present at different levels in 46% of tumours and did not correlate with PTEN protein expression. HER3 expression positively (p=0.0128) and pEGFR (p=0.0143) negatively correlated with HPV. HER4, pAkt, Akt and PTEN expression were not related to HPV.
Conclusions: HER3 and HER4 are the main HER receptors involved in PC. Both receptors work through the Akt1 pathway and may lead to increased tumour grade. EGFR may play a role in early stages of the disease. HER2 is not involved in penile carcinogenesis. HPV-positive tumours mainly rely on the HER3 receptor to activate Akt pathway, while HPV-negative cancers seem to depend more on EGFR.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 11:45 AM
Platform Session: Section A, Monday Morning