Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4

A major contributor to the significant recent decline in breast cancer mortality is the use of adjuvant endocrine therapy. However, the overall efficacy of tamoxifen, aroma tase inhibitors, and the pure antiestrogen, fulvestrant, is limited by de novo and acquired resistance. The article by Hutcheson and colleagues [1] in the previous issue of Breast Cancer Research further develops our understanding of the role of the ErbB family in endocrine resistance by providing new insights into the roles of ErbB-3 and -4 in modulating sensitivity to fulvestrant.Since endocrine resistance may compromise the effective treatment and potential cure of up to 25% of all breast cancers, defining the mechanisms of endocrine resistance has been a major research focus. This body of research identifies a wide range of biological mechanisms that can confer endocrine resistance in vitro. These include the following: loss of estrogen receptor-alpha (ER？) expression and expression of truncated isoforms of ER？ and ER？ post-translational modification, particularly phosphorylation of ER？; increased activity of other transcription factors, including AP1 and c-Myc; deregulation of ER coactivators; and increased receptor tyrosine kinase signaling with resultant activation of the ERK and PI3K pathways and deregulation of the cell cycle, cell survival, and apoptotic machinery [2]. Although the direct relevance of these in vitro mechanisms to endocrine resistance in the clinic is far from clear, data accumulated in recent years provide strong evidence for a direct role for ErbB-2.Since the initial observation that increased levels of both the epidermal growth factor receptor (EGFR/ErbB-1) and ErbB-2 activate an autocrine growth-stimulatory pathway in tamoxifen-resistant MCF-7 cells [3], a number of laboratories have replicated and extended these findings. Thus, upregulation of ErbB-1 and -2 are common features of endocrine-resistant breast cancer cells, overexpression of these receptors confers inse