High Oxytocin Receptor Expression Linked to Increased Cell Migration and Reduced Survival in Patients with Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and high mortality. The oxytocin receptor (OTR) is a class-A G protein-coupled receptor that has been linked to breast cancer, but its role in tumorigenesis and disease progression remains underexplored. OTR expression is highest in tumour-adjacent breast tissue, followed by normal and tumour tissue, indicating a potential role in the tumour microenvironment. OTR levels were higher in migrated MDA-MB-231 cells than in the control parental cells cultured in normal medium; OTR overexpression/knock-down and metastasis biomarker experiments revealed that high OTR expression enhanced metastasis capabilities. These findings align well with data from a murine breast cancer metastasis model, where metastasised tumours had higher OTR expression than the corresponding primary tumours, and high OTR expression also correlates to reduced survival in TNBC patients. OTR agonists/antagonists did not affect MDA-MB-231 cell migration, and pharmacological analysis revealed that the OT/OTR signalling was compromised. High OTR expression enhanced cell migration in an OTR ligand-independent manner, with the underlying mechanism linked to the EGF-mediated ERK1/2-RSK-rpS6 pathway. Taken together, high OTR expression seems to be involved in TNBC metastasis via increasing cell sensitivity to EGF. These results support a potential prognostic biomarker role of OTR and provide new mechanistic insights and opportunities for targeted treatment options for TNBC.