The HER4/ERBB4 gene is located on chromosome 2q33.3–34 and the encoded protein can be activated by both NRGs and some ligands of the EGF family (betacellulin, epiregulin, heparinbinding EGF-like ligand). HER4/ERBB4 expression is detectable in less than half of breast cancers. In contrast to the other HER receptors, the existing evidence suggests that HER4/ERBB4 is characterized by antiproliferative and pro-apoptotic activity. In cell line experiments, when HER2 positive cancer cells were transfected to overexpress HER4/ERBB4, a reduction in proliferation and an increase in apoptosis was noted, possibly indicating that HER4/ERBB4 antagonizes HER2 signalling activity. HER4/ERBB4 is a unique cell surface receptor and mediates completely novel activities for a transmembrane tyrosine kinase. Four isoforms of HER4/ERBB4 receptor have been described (JMa or JMb, Cyt1 or Cyt2), resulting from alternative splicing of HER4/ERBB4 mRNA. The JMa isoform contains an extracellular proteolytic site, which could be cleaved by the metalloproteinase tumor necrosis factor-alpha converting enzyme (TACE). After cleavage by TACE, the remaining transmembrane cleavage product (m80) could undergo a second intramembrane -secretase cleavage releasing into the cytoplasm a soluble HER4/ERBB4 intracellular domain (4ICD). The 4ICD may either remain in the cytosol or translocate to the nucleus. The intracellular domain of HER4/ERBB4 is characterized by multiple, diverse biological activities and cellular responses including differentiation of mammary epithelial cells and lactation, activation of pro-apoptotic pathways, cell cycle arrest, modulation of transcription through formation of complexes with transcription factors and cell proliferation. In addition, it has been demonstrated that these diverse responses are associated with the localization of 4ICD in different cell compartments. Nuclear 4ICD functions as a potent ER co-activator, directly interacting with ligandassociated ER and promoting the proliferation of ER positive breast tumor cells. On the other hand, cytosolic 4ICD accumulates within mitochondria, promoting apoptosis of tumor cells through the activity of the cell-killing BH3 domain. Therefore, manipulation of 4ICD cell localization could be a potentially effective therapeutic strategy in breast cancer patients. Another therapeutic approach in breast cancer relates to the simultaneous inhibition of all members of the HER family using TKIs such as canertinib. Nevertheless, considering that a number of studies strongly support that HER4/ERBB4 correlates with improved prognosis in breast cancer patients, the use of pan-HER targeted treatments could possibly abate the beneficial effect of HER4/ERBB4 on patient outcome.
Koutras A K, Fountzilas G, Kalogeras K T, et al. The upgraded role of HER3 and HER4 receptors in breast cancer[J]. Critical reviews in oncology/hematology, 2010, 74(2): 73-78.