Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis

Breast Cancer Research

Adrian L Harris³  Chris J Norbury³  Mike J Bradburn²  Russell D Leek¹  Zoë E Winters⁴ 

[1] Cancer Research UK Tumour Pathology Group, University of Oxford, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, UK;Cancer Research UK Medical Statistics Group, Centre for Statistics in Medicine, Institute of Health Sciences, Oxford, UK;Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK;University Department of Surgery, Bristol Royal Infirmary, University of Bristol, UK

关键词: prognostic markers;    phosphatidylinositol-3 kinase/protein kinase B;    immunohistochemistry;    CDK inhibitor;   

Others  :  1118785
DOI  :  10.1186/bcr654

 received in 2003-06-09, accepted in 2003-09-02,  发布年份 2003

【 摘 要 】

Background

HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21^WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21^WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21^WAFI/CIPI. We previously showed that higher levels of cytoplasmic p21^WAFI/CIPI in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21^WAFI/CIPI expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome.

Methods

The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21^WAFI/CIPI staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA).

Results

HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21^WAFI/CIPI staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21^WAFI/CIPI and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21^WAF1/CIP1 and HER-2.

Conclusion

This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21^WAFI/CIPI from the nucleus to the cytoplasm, resulting in a loss of p21^WAFI/CIPItumour suppressor functions. Cytoplasmic p21^WAFI/CIPI may be a surrogate marker of functional HER-2 in vivo.

【 授权许可】

   
2003 Winters et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

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