Angiopoietin1 Promotes Triple-negative Breast Cancer Cell Proliferation By Upregulating CPA4 In A Non-secreted Manner

Breast cancer is a serious threat to women’s life and health due to its high incidence and perennial high mortality rate.According to the expression of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor(HER2),breast cancer can be classified into four subtypes: Luminal A,Luminal B,HER2 overexpressing and triple-negative breast cancer(TNBC),of which TNBC accounts for about 20% of all breast cancer.In recent years,with the rise of medical care,cancer treatment has been improved,but the prognosis of triple-negative breast cancer is poor due to the lack of very effective therapeutic targets,susceptibility to distant metastasis and drug resistance.Tumor angiogenesis plays an important role in its development by providing sufficient oxygen and nutrients to tissues that are progressively larger in volume and hypoxic.The reported cytokines promoting tumor angiogenesis include Vascular endothelial growth factor(VEGF)and Angiopoietin(ANGPT,ANG)family,which can promote tumor growth by regulating vascular regeneration and development.Angiopoietin1(ANG1),a member of the angiopoietin family,is normally secreted by perivascular cells,binds to tyrosine kinase receptor2(Tie2)on vascular endothelial cells,and plays important roles in vascular integrity and remodeling,vasodilation,and anti-inflammation.However,the function and mechanism of ANG1 in triple-negative breast cancer is not well studied.Clinical sample databases showed that ANG1 levels were higher and suggestive of poor prognosis in TNBC compared to non-TNBC.In addition,our study demonstrated that ANG1 promotes cell proliferation,cell cycle progression and anti-apoptosis in triple-negative breast cancer cells by up-regulating Carboxypeptidase A4(CPA4)in a non-secreted manner.The results of nude mice transplantation tumor experiments showed that ANG1 overexpression could promote tumor growth in vivo.Mechanistically,we suggest that ANG1 promotes the progression of triple-negative breast cancer through upregulation of CPA4.These results indicate that the ANG1/CPA4 axis has the potential to be a therapeutic target for triple-negative breast cancer.