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

Copyright: 2011 Stankiewicz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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.Peer reviewedFinal Published versio

Understanding factors that inhibit or promote the utilisation of telecare in chronic lung disease

Objectives To perform a process evaluation of a randomized controlled trial (RCT) of home telecare for the management of acute exacerbations of chronic obstructive pulmonary disease (COPD), using the normalization process model (NPM) as an explanatory framework. Methods Semi-structured interviews were carried out with patients (n = 9) and nurses (n = 11) participating in a RCT. A framework approach to data analysis was used. Results The telecare service did not provide an interactional advantage for the nurses providing this service and did not fit with the nurses' views of the most appropriate or preferred use of their skills. The telecare service seemed unlikely to become normalized as part of routine healthcare delivery, because the nursing team lacked confidence that it was a safe way to provide healthcare in this context and it was not perceived as improving efficiency. Discussion The NPM effectively mapped onto the study findings and explained those factors that inhibited the routine delivery of COPD services by telecare

Specific antibody detection of expressed proteins in penile tumours with known HPV status.

<p>P values show difference between HPV-positive and negative tumours.</p>1<p>p, phosphorylated, active protein.</p>2<p>m, membranous expression.</p>3<p>n, nuclear expression.</p>4<p>cyt, cytoplasmic expression.</p

<i>EGFR</i> and <i>PTEN</i> copy number status using fluorescent <i>in situ</i> hybridisation.

<p><i>EGFR</i> gene copy number gain (arrows) but no amplification signal clusters are present in some tumours (A). <i>PTEN</i> gene copy number loss (arrows) is present in a small fraction of tumour cells (B).</p

Immunoexpression of pEGFR, HER3, HER4, pAkt, Akt1 and PTEN proteins in PSCC.

<p>Strong immunoexpression of pEGFR (A), HER3 (B) and HER4 (C). pAkt (D) and Akt1 (E) show both nuclear and cytoplasmic staining. PTEN expression is restricted to nuclei only and reduced staining was often found in cancer cells (F). <i>Scale bar</i>: 50 µm.</p

Antibody detection of expressed proteins in correlation with grade and stage of penile tumours.

1<p>Ab, antibody.</p>2<p>p, phosphorylated, active protein.</p>3<p>m, membranous expression.</p>4<p>n, nuclear expression.</p>5<p>cyt, cytoplasmic expression.</p