Oxytocin receptor and HER2 interactions in breast cancer

Abstract Breast cancer affects women globally, with HER2 being one of the most aggressive subtypes. Despite advances in HER2-targeted therapies, many patients fail to respond to such treatments. In search of alternative therapeutic targets, we investigated the role of the oxytocin (OT) and oxytocin receptor (OTR) signalling system in HER2 + breast cancer. Survival analysis of HER2 subtype breast cancer patients revealed high OTR expression correlating with significantly improved relapse-free survival. OTR overexpression or knockdown in HER2 + SK-BR-3 cells decreased or increased cell viability, respectively. HER2 was downregulated in OTR-overexpressing cells, which could contribute to the decreased Pertuzumab efficacy. Importantly, HER2 was internalised upon OT treatment and interacted with OTR to form OTR-HER2 complexes. OT treatment furthermore induced a transient inhibition of HER2 phosphorylation without affecting the total HER2 protein levels. In addition, OT inhibited ERK1/2 phosphorylation but enhanced Akt phosphorylation, linked to increased cell viability. In summary, this work describes a novel HER2-OTR interaction and mechanism, expanding our understanding of HER2 cancer biology that might lead to new prognostic and therapeutic opportunities centred around the OT/OTR signalling system for patients suffering from HER2 + breast cancer.