title: Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry.
abstract: The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-κB/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis.
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Changhui
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: xiaojingmeng@smu.edu.cn.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: zoufei616@163.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Zou
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D020013:Calcium Signaling; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D014162:Transfection; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D016328:NF-kappa B; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000071250:Snail Family Transcription Factors; D000803:Angiotensin I; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)
keywords: ACE2/Ang-(1–7)/Mas axis; Breast cancer metastasis; E-cadherin; PAK1/NF-κB/Snail1 pathways; Store-operated calcium entry (SOCE)