The localization of HER4 intracellular domain and expression of its alternately-spliced isoforms have prognostic significance in ER+HER2-breast cancer

Human epidermal growth factor receptors (HERs) are known to play a pivotal role in breast cancer, both as prognostic markers and as therapeutic targets. The importance of Her4 expression is, however, still controversially discussed; there are few reports on the clinical significance of HER4, its splice variants, and cleaved HER4 intracellular domains (4ICD) which function differently depending on their localization in breast cancer. In 238 primary invasive breast cancer patients, we analyzed the expression levels of HER4 extracellular (JM-a and JM-b) and intracellular (CYT-1 and CYT-2) domains as well as 4ICD localization, and tested the relationship with clinicopathological characteristics and prognosis. The predominantly-expressed extracellular domain was JM-a, and lower CYT-2 dominance was a factor related to better relapse-free survival. CYT-2-dominance with higher nuclear 4ICD expression was a favorable prognostic marker especially in patients with the ER+ HER2- subtype treated with endocrine therapy. The absence of cytoplasmic 4ICD staining was related to better prognosis in CYT-1-dominant patients. In conclusion, analysis of splicing variants and 4ICD localization should be considered when targeting HER4 as a novel ER+/HER2- breast cancer treatment.