HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer

The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities.