Abstract
Oxytocin receptor (OXTR) is involved in social behaviors, thermoregulation, and milk ejection, yet little is known about its role in breast cancer. To investigate the role of OXTR in mammary gland development and tumorigenesis, a transgenic mouse model of OXTR overexpression (++Oxtr) was used. Overexpression of OXTR-induced progressive mammary hyperplasia, unexpected milk production, and tumorigenesis in females. OXTR-induced mammary tumors showed ERBB2 upregulation and mixed histological subtypes with predomination of papillary and medullary carcinomas. OXTR overexpression led to an activation of prolactin (PRL)/p-STAT5 pathway and created a microenvironment that promotes mammary-specific tumorigenesis. PRL inhibitor bromocriptine (Br) could mitigate OXTR-driven mammary tumor growth. The study demonstrates Oxtr is an oncogene and a potential drug target for HER2-type breast cancer.
Highlights
Breast cancer is the most common cancer with highest morbidity among females worldwide[1]
Erbb[2], Akt[1], and Tgfα upregulated in ++Oxtr tumors displayed clear enrichment of signal transducer and activator of transcription 5 (STAT5) (Fig. 4I)[32,33,34]. These results suggest that activation of PRL/p-STAT5/RANKL pathway is likely mediating Oxytocin receptor (OXTR)-induced mammary tumorigenesis
STAT5 leads to increased transcription of mammary epithelial proliferation-related genes, accelerated mammary gland development, and tumorigenesis (Fig. 7)
Summary
Breast cancer is the most common cancer with highest morbidity among females worldwide[1]. It is genetically classified into four subtypes, HER2+, Luminal A, Luminal B, and triple negative (basal-like subtype)[2]. These subtypes differ significantly in prognosis and responsiveness to various therapeutic options[3]. HER2 is overexpressed in 20–30% of breast tumors[5] and correlates with poor patient outcome[6]. A tyrosine kinase inhibitor, mitigates mammary tumor growth by blocking HER2 tyrosine kinase activity[7]. Understanding breast cancer development is critical for effective treatments.
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