"Shedding" light on HER4 signaling in normal and malignant breast tissues

Receptor Tyrosine Kinases of the Epidermal Growth Factor Receptor Family play a pivotal role as drivers of carcinogenesis and uncontrolled cell growth for a variety of malignancies, not least for breast cancer. Besides the estrogen receptor, the HER2 receptor was and still is a representative marker for advanced taxonomic sub-differentiation of breast cancer and emerged as one of the first therapeutic targets for antibody based therapies. Since the approval of trastuzumab for the therapy of HER2-positive breast cancer in 1998 anti-HER2 treatment strategies are being modified, refined, and successfully combined with complementary treatments, nevertheless there is still potential for improvement. The HER2 relatives, namely HER1 (i.e., EGFR), HER3 and HER4 share a high degree of molecular homology and together form a functional unit for signal transmission. Under regular conditions, receptor coexpression patterns and receptor interaction represent key parameters for signaling robustness, which ensures cellular growth control and enables tissue differentiation. In addition, treatment efficiency of e.g., an anti-HER2 targeting is substantially determined by the expression pattern of HER receptors on target cells. Within the receptor family, the HER4 plays a particular role and is engaged in exceptional signaling activities. A favorable prognostic impact has been attributed to HER4 expression in breast cancer under specific molecular conditions. HER4-specific cellular effects are initially determined by a ligand-dependent or -independent receptor activation. Essential processes as cell growth and proliferation, cell differentiation, and apoptotic cell death can be initiated by this receptor. This review gives an overview of the role of HER4 in normal and malignant breast epithelial cells and tissues. Specific mechanism of HER4 activation and subsequent intracellular signaling will be described by taking a focus on effects provoked by receptor shedding. HER4 activities and specific effects will be correlated to breast cancer subtypes and the impact of HER4 on course and outcome of disease will be considered. Moreover, current and potential therapeutic approaches will be discussed.