Abstract

Background: Human epidermal growth factor receptor-4 (HER4) and yes-associated protein-1 (YAP) are candidate therapeutic targets in oncology. YAP's transcriptional coactivation function is modulated by the HER4 intracellular domain (HER4-ICD)in vitro, but the clinical relevance of this has not been established. This study investigated the potential for targeting the HER4-YAP pathway in brain metastatic breast cancer. Methods: We performed immuno-phenotypic profiling of pathway markers in a consecutive breast cancer series with 25 years of clinical follow up (n = 371), and patient-matched breast and metastatic brain tumours (n = 91; 30 pairs). Results: Membrane localisation of phospho-HER4 [pHER4(Y-1162)] was infrequent in primary breast cancer, but very frequent in brain metastases (5.9%versus75% positive), where it was usually co-expressed with pHER3(Y-1289) (p < 0.05). The presence of YAP in tumour cell nuclei was associated directly with nuclear pERK5(T-218/Y-210) (p = 0.003). However, relationships with disease-specific survival depended on oestrogen receptor (ER) status. Nuclear pYAP(S-127) was associated with smaller, good prognostic ER+ breast tumours (log-rank hazard-ratio 0.53;p = 9.6E(-03)), but larger, poor prognostic triple-negative cancers (log-rank hazard-ratio 2.78;p = 1.7E(-02)), particularly when co-expressed with nuclear HER4-ICD (p = 0.02). This phenotype was associated with stemness and mitotic instability markers (vimentin, SOX9, ID1, SPAG5, TTK, geminin;p < 0.05). YAP expression in brain metastases was higher than matched primary tumours; specifically, nuclear pYAP(S-127) in ER-negative cases (p < 0.05). Nuclear YAP was detected in similar to 70% of ER-negative, HER4-activated brain metastases. Discussion: Our findings suggest that the canonical-mechanism where Hippo pathway-mediated phosphorylation of YAP ostensibly excludes it from the nucleus is dysfunctional in breast cancer. The data are consistent with pYAP(S-127) having independent transcriptional functions, which may include transducing neuregulin signals in brain metastases. Consistent with mechanistic studies implicating it as an ER co-factor, nuclear pYAP(S-127) associations with breast cancer clinical outcomes were dependent on ER status. Conclusion: Preclinical studies investigating HER4 and nuclear YAP combination therapy strategies are warranted.

Authors	Kalita-de Croft, Priyakshi; Lim, Malcolm; Chittoory, Haarika; de Luca, Xavier M.; Kutasovic, Jamie R.; Day, Bryan W.; Al-Ejeh, Fares; Simpson, Peter T.; Reed, Amy E. McCart; Lakhani, Sunil R.; Saunus, Jodi M.
Journal	Therapeutic Advances in Medical Oncology
Pages	1758835920946259
Volume	12
Date	1/07/2020
Grant ID	APP1017028
Funding Body	Australian National Health and Medical Research Council
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1177/1758835920946259