title: Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas.
abstract: 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).
  
  
  RESULTS
  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
  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.
authors.affiliation: 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. e.stankiewicz@qmul.ac.uk
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Stankiewicz
authors.forename: David M
authors.initials: DM
authors.lastname: Prowse
authors.forename: Mansum
authors.initials: M
authors.lastname: Ng
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.forename: David
authors.initials: D
authors.lastname: Mesher
authors.forename: Frances
authors.initials: F
authors.lastname: Hiscock
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Watkin
authors.forename: Catherine
authors.initials: C
authors.lastname: Corbishley
authors.forename: Wayne
authors.initials: W
authors.lastname: Lam
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Berney
mesh_terms: D000912:Antibodies, Neoplasm / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology*; D010412:Penile Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000912:Antibodies, Neoplasm; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human