Medicine in focus
Breast cancer: The upgraded role of HER-3 and HER-4

https://doi.org/10.1016/j.biocel.2006.11.017Get rights and content

Abstract

Breast cancer is the most common cancer in women and the ErbB receptor family holds crucial role in its pathogenesis. Among them, epidermal growth factor receptor and HER-2 are the most studied members and their overexpression has been associated with aggressive clinical behaviour. These data were further strengthened by the clinical success of trastuzumab, a monoclonal antibody against HER-2 in breast cancer patients with HER-2 overexpression and/or amplification. However, trastuzumab failure in some patients may partly be attributed to co-expression of other ErbB receptors. Herein, we provide updated views regarding the role of HER-3 and HER-4 in breast cancer. Accumulated evidence implies that these receptors should be considered more than heterodimerisation partners. Their expression profile might be useful in predicting responsiveness to current treatment options, while new strategies targeting their ligands and downstream effectors are being developed.

Introduction

The hallmark of breast cancer is the great heterogeneity rendering its treatment complex. Certain clinical characteristics have been used to predict which patients are likely to have favourable or unfavourable course. Molecular prognostic and predictive factors have been also extensively evaluated to assist tailored treatment of breast cancer more than for any other solid tumour (Karamouzis et al., 2002). However, the development of optimal consensus treatment guidelines for breast cancer requires both the comprehensive analysis of the results of randomized clinical trials and the interpretation of their clinical and biological relevance for individual patients (Goldhirsch et al., 2005). Molecular markers of prognosis and prediction in breast cancer are still considered less than ideal (Hayes, 2005). Recently, major research efforts have focused on identifying novel valuable markers, expression profiles and/or genetic “fingerprints” that could potentate the efficacy of current and future treatment regimens.

Section snippets

The ErbB receptor family in breast cancer

The transmembrane receptors that bear tyrosine kinase (TK) activity play a key role in breast cancer. The type I TK receptor family comprises four homologous members: ErbB-1 [epidermal growth factor (EGF) receptor (EGFR) or HER-1], ErbB-2 (HER-2/neu), ErbB-3 (HER-3) and ErbB-4 (HER-4). All family members have intrinsic TK activity, except for HER-3 (Fig. 1). The phosphorylation of these receptors (evoked by ligand binding and homo-or heterodimerisation) ignites a cascade of signalling pathways

Therapy

In recent years, significant treatment advances parallel the increased detection of breast carcinomas in earlier and more curable stages. In conjunction to the refinement of conventional treatment modalities, the identification of HER-2 as an important regulator of breast cancer cell proliferation led to the development of strategies aiming at reducing HER-2 receptor levels or activity, with the more successful being trastuzumab. However, certain aspects related to trastuzumab await

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