Immunophenotyping of HER4/YAP axis in breast cancer brain metastasis

Abstract

Brain metastasis (BrM) is a devastating diagnosis for patients with breast cancer. Identification of immunophenotypical features specific to BrM is crucial for developing effective new therapeutic interventions. Yes-associated protein (YAP) mediates downstream effects of the neuregulin receptor, HER4, on breast cancer cell proliferation in vitro. HER4 is frequently over-expressed in BrM, but the relationship with YAP has not been investigated. This study examined the HER4/YAP axis in patient samples (n=41) from matched primary breast and metastatic brain tumours. Immunohistochemistry analysis revealed HER4 was highly phosphorylated in BrM compared to matched primary tumours (p=0.0022), and this was strongly associated with expression and phosphorylation of dimerization partners HER2 and HER3 (p<0.0001). When compared to a general breast cancer cohort (n=373), we found HER4 activation to be brain metastasis specific (p<0.0001). However, YAP was frequently phosphorylated in both HER4-activated primary breast tumours and brain metastases, suggesting that pro-proliferative YAP signaling is not a major consequence of HER4 activation in these tumours. These results display the complexity of expression of the HER family receptors and the downstream pathways in BrM and suggest simultaneous targeting of multiple receptors might be more advantageous.