Alternative HER/PTEN/Akt Pathway Activation in HPV Positive and Negative Penile Carcinomas

PLoS One

Jack Cuzick¹  David Mesher¹  Yong-Jie Lu²  Frances Hiscock²  Daniel M. Berney²  David M. Prowse²  Elzbieta Stankiewicz²  Mansum Ng²  Catherine Corbishley³  Wayne Lam³  Nicholas Watkin⁴ 

[1] Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London, Queen Mary University of London, United Kingdom;Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;The Cellular Pathology Department, St George's Hospital, Tooting, London, United Kingdom;The Department of Urology, St George's Hospital, Tooting, London, United Kingdom

关键词: Cancer treatment;    Human papillomavirus infection;    Protein expression;    Fluorescent in situ hybridization;    Squamous cell carcinomas;    Carcinogenesis;    Human papillomavirus;    Carcinomas;   

DOI  :  10.1371/journal.pone.0017517

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH). Methodology/Principal Findings 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs. Conclusions/Significance EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection. Our results suggest that PSCC patients could benefit from therapies developed to target HER receptors.

【 授权许可】

CC BY