Functional Analysis Of Oxytocin Receptor (OXTR) In Mammary Gland Development And Tumorigenesis

Breast cancer is a malignant tumor with the highest morbidity and mortality among women worldwide.Studies on molecular mechanism of breast cancer can provide theoretical basis for clinical diagnosis and treatment.Transgenic mouse models of mammary carcinomas are powerful tools in analyzing breast cancer development and progression.Oxytocin Receptor(OXTR)is a G protein-coupled receptor with 7 transmembrane domains,known to be expressed in mammary gland,kidney,uterine myometrium,cardiac muscle of heart,vascular endothelium layer and specific brain regions.OXTR is known to be involved in maternal behavior,social behaviors,energy metabolism,thermoregulation and milk yield.OXTR expression has been detected in a number of human breast tumors and breast cancer cell lines,suggesting its possible involvement in breast cancer.However,its roles and regulatory mechanism in mammary gland development and tumorigenesis have not been reported.To define the functions of OXTR,a transgenic mouse model that overexpresses mouse Oxtr under?-Actin promoter was generated(⁺⁺Oxtr).Our study shows OXTR overexpression induces abnormal mammary gland development and tumorigenesis.Overexpression of OXTR inhibited progesterone secretion,but increased prolactin-induced STAT5 activation,leading to accelerated mammary gland development and early milk production at non-pregnancy and early pregnancy.In lactation,⁺⁺Oxtr mice exhibited decreased prolactin-induced STAT5phosphorylation,resulting in a severe impairment in mammary gland differentiation,early involution of alveolar and failure of nurturing.The abnormal mammary gland development was possibly from hormonal changes induced by brain OXTR overexpression,not by mammary gland OXTR overexpression.Progesterone and prolactin pathway functions as mediators between OXTR and mammary gland development.3-month-old⁺⁺Oxtr females exhibited progressive mammary hyperplasia and unexpected early milk production.About 57%⁺⁺Oxtr females developed mammary tumors from age of 5month to 15 month.Tumors showed Her2 overexpression and mixed histological subtypes with predomination of papillary and medullary carcinomas.OXTR overexpression leads to activation of PRL/p-STAT5 signaling and creates a microenvironment that promotes mammary tumorigenesis and metastasis.Bromocriptine can mitigate OXTR-driven hyper-mammogenesis and mammary tumor growth and may be an effective drug of treatment of breast cancer.Our results provide compelling evidence that OXTR overexpression induces hormonal changes in⁺⁺Oxtr females,leading to abnormal mammary gland development and tumorigenesis.It offers novel insights into the important roles of OXTR in mammary gland development and tumorigenesis.⁺⁺Oxtr mouse can be used as a new model for screening and testing drugs of breast cancer,which provides new ideas for clinical diagnosis and treatment.