Angiotensin-(1-7) reduces fibrosis in orthotopic breast tumors

Cancer Res. 2010 Nov 1;70(21):8319-28. doi: 10.1158/0008-5472.CAN-10-1136. Epub 2010 Sep 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Ductal, Breast / prevention & control*
  • Dual Specificity Phosphatase 1 / metabolism
  • Female
  • Fibronectins / metabolism
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fibrosis / prevention & control
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Lung Diseases, Interstitial / metabolism
  • Lung Diseases, Interstitial / pathology
  • Lung Diseases, Interstitial / prevention & control*
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Transforming Growth Factor beta / metabolism
  • Tumor Cells, Cultured


  • Antihypertensive Agents
  • Fibronectins
  • Peptide Fragments
  • Transforming Growth Factor beta
  • Angiotensin I
  • Mitogen-Activated Protein Kinase 3
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • angiotensin I (1-7)