ReviewERBB2 oncogene in human breast cancer and its clinical significance
Introduction
The ERBB2 oncogene1, 2, also called HER2/neu[3], is the human homologue of the neu oncogene identified in DNA from rat neuroglioblastomas induced by ethyl-nitroso-urea[4]. Located on chromosome 17q, the gene encodes a trans-membrane glycoprotein (p185) with tyrosine kinase activity, which is closely related to epidermal growth factor receptor (EGFR)[5]. These proteins, together with those encoded by ERBB3 (HER3)6, 7and ERBB4 (HER4)[8], constitute the type I growth factor receptor gene family9, 10.
All four members of the family are expressed in breast cancer cells in vitro. For primary breast cancer, since increased levels of EGFR[11]and ERBB2[12]were first reported, several thousand cases have been studied and the clinical significance of EGFR has been extensively examined[13]. Elevated expression of ERBB3 has been observed14, 15, 16, but until now this has been poorly documented. Although isolated from breast cancer cells, ERBB4 expression has not yet been assayed in breast cancers.
Despite the numerous studies, the prognostic significance and the value of ERBB2 in predicting the response to treatment remain somewhat unclear. Here we review the biological and clinical data on ERBB2 in breast cancer and discuss the clinical usefulness of this parameter.
Section snippets
Analytical review method
For this paper, the review of Klijn and associates[13]on EGFR in breast cancer, was used as a model. We selected the papers reporting relevant data on one or more of the clinical aspects of ERBB2 in breast cancer. The source of the articles was the Cancerlit database. When the same group published several papers with increasing numbers of patients, we used the most recent paper. We found 97 different studies involving 22 616 patients. The relationship between ERBB2 and prognosis was described in
ERBB2 activation in human breast cancer
In human breast cancer, activation of the ERBB2 proto-oncogene by translocation has not yet been described, and rearrangements of ERBB2 have rarely been observed[12]. Activating trans-membrane point mutations, observed in the rat homologue neu oncogene[17], have not been found in human breast cancer[18]. The main mechanism of ERBB2 activation involves amplification, which has always been associated with overexpression, as revealed by increased levels of p185 and its mRNA12, 19. However, it
ERBB2 positivity in human breast cancer
Amplification of the ERBB2 gene was evaluated in most of the studies by Southern blot (34 studies, Table 1) and in recent reports by the polymerase chain reaction (PCR) method (five studies; Table 1). Overexpression has been determined by various methods (Table 2), including Northern blot (six studies), fluorescent in situ hybridisation (one study), Western blot (six studies), flow cytometry (one study) and immunohistochemistry (57 studies). The immunohistochemical staining, using at least 17
Hormonal receptor status
The mean ERBB2 positivity is 2.4 times higher in oestrogen receptor (ER) negative than in ER positive tumours (35.5% versus 13.3%), and it is twice as high in progesterone receptor (PR) negative than in PR positive tumours (32.2% versus 14.8%) (Table 4). Accordingly, Heintz and colleagues[40]reported that 79 and 61% of ERBB2 negative tumours were, respectively, ER and PR positive, whilst only 53 and 24% of ERBB2 positive tumours were ER and PR positive. Todd and associates[50]observed that ER
Prognostic value of ERBB2
The relationship between ERBB2 positivity and clinical outcome in primary breast cancer was examined, taking into consideration both the whole population of patients (lymph node-positive and negative patients, Table 7) and the two subpopulations of patients separately (lymph node positive patients, Table 8; lymph node negative patients, Table 9). In all the studies, the well accepted prognostic factors, such as the number of involved lymph nodes, the steroid receptors, histopathological grading
Hormonotherapy
When considering node-positive, steroid positive tumour patients, Borg and colleagues[58]noted a favourable effect of adjuvant tamoxifen on survival for patients with ERBB2 negative tumours, while patients with ERBB2 positive tumours did not benefit from tamoxifen administration. Giai and associates[72]observed that node positive breast cancer patients co-expressing ERBB2 and RAS had a worse outcome than patients not co-expressing these oncogenes, when treated with tamoxifen. Recently,
Hormonotherapy
Wright and colleagues[106]reported that among patients receiving endocrine therapy as first-line treatment for relapse, 7% of ERBB2 positive patients responded to tamoxifen treatment compared with 37% of ERBB2 negative patients (P<0.05). Moreover, ERBB2 and EGFR appeared to have an additive effect in reducing the likelihood of response, since 0 of 8 patients with EGFR and ERBB2 positive tumours benefitted from endocrine therapy[106]. Similarly, Nicholson and colleagues[110]observed ERBB2
Therapeutic perspectives
As several lines of evidence have suggested that breast cancer patients with ERBB2 overexpression exhibit a reduced response to conventional treatments, new therapeutic approaches, targeting the cells overexpressing ERBB2 and based on monoclonal antibodies (MAbs) or on antisense technology, have been developed.
In the first approach, murine MAbs directed against the extracellular domain of p185 have been shown to inhibit the growth, in cell lines and in xenograft models, of human breast cancer
Conclusion
The variations in ERBB2 positivity in human breast cancer were analysed taking into account the different methods used for evaluation. The range of ERBB2 positivity described in the different papers was very wide in every method. In immunohistochemical studies, a probable explanation for the variable overexpression rates reported in the literature was provided by Press and colleagues[187], who demonstrated the highly variable ability of the ERBB2 antibodies to detect overexpression in archival
Acknowledgements
Supported by grants from the Ligue Nationale Contre le Cancer (LNCC, Paris) and the Comité Départemental du Nord of the LNCC (Lille); by the Groupement Intérregional de Recherche en Cancérologie (ARERS funds, Reims) and by the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC Flandres-Artois). The authors are grateful to Susan Richardson for the English corrections.
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