Angiotensin-(1-7) reduces fibrosis in orthotopic breast tumors.
Angiotensin-(1-7) [Ang-(1-7)] is an endogenous 7-amino acid peptide hormone of the renin-angiotensin system that has antiproliferative properties. In this study, Ang-(1-7) inhibited the growth of cancer-associated fibroblasts (CAF) and reduced fibrosis in the tumor microenvironment. A marked decrease in tumor volume and weight was observed in orthotopic human breast tumors positive for the estrogen receptor (BT-474 or ZR-75-1) and HER2 (BT-474) following Ang-(1-7) administration to athymic mice. Ang-(1-7) concomitantly reduced interstitial fibrosis in association with a significant decrease in collagen I deposition, along with a similar reduction in perivascular fibrosis. In CAFs isolated from orthotopic breast tumors, the heptapeptide markedly attenuated in vitro growth as well as reduced fibronectin, transforming growth factor-β (TGF-β), and extracellular signal-regulated kinase 1/2 kinase activity. An associated increase in the mitogen-activated protein kinase (MAPK) phosphatase DUSP1 following treatment with Ang-(1-7) suggested a potential mechanism by which the heptapeptide reduced MAPK signaling. Consistent with these in vitro observations, immunohistochemical analysis of Ang-(1-7)-treated orthotopic breast tumors revealed reduced TGF-β and increased DUSP1. Together, our findings indicate that Ang-(1-7) targets the tumor microenvironment to inhibit CAF growth and tumor fibrosis.
Cook
Katherine L
KL
Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Metheny-Barlow
Linda J
LJ
Tallant
E Ann
EA
Gallagher
Patricia E
PE
D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D017563:Lung Diseases, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000959:Antihypertensive Agents; D005353:Fibronectins; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D000803:Angiotensin I; D048052:Mitogen-Activated Protein Kinase 3; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C118790:angiotensin I (1-7)