Breast cancer is the most common type of cancer in women and the second leading cause of death, with approximately 40,000 deaths each year. Triple negative breast cancer, which accounts for 10-15% of all breast cancers, disproportionately affects younger women as well as women of African-American and Hispanic descent. Triple negative breast cancer cells do not express estrogen or progesterone receptors nor over-express human epidermal growth factor receptor 2 (HER2) and thus do not respond to targeted therapies, limiting treatment options to cytotoxic drugs. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, seven amino acid peptide hormone of the renin-angiotensin system which inhibits cell growth by activation of the unique G protein-coupled receptor mas. We showed that Ang-(1-7) significantly reduced the in vivo growth of human triple negative MDA-MB-231 breast tumors in an orthotopic model, with a significant decrease in both tumor volume and wet weight compared with saline controls. The heptapeptide inhibited cell proliferation, reducing Ki67 immunoreactivity and activity of the mitogen-activated protein kinases ERK1 and ERK2 in triple negative breast tumors. Ang-(1-7) also reduced the phosphorylation of Akt (protein kinase B), which is phosphorylated by phosphoinositide-dependent kinases in response to receptor-mediated activation of phosphatidylinositol-3-kinase (PI3 kinase), to stimulate cell proliferation and increase cell survival. The heptapeptide reduced Ser473 phospho-Akt in MDA-MB-231 cells by 65%, with a maximal effect at 4 h, in agreement with a 51% reduction in phospho-Ser473 in MDA-MB-231 tumors in mice treated with Ang-(1-7). Phospho-Thr308 Akt was also reduced approximately 45% by treatment of MDA-MB-231 cells with Ang-(1-7), with a maximal effect after 4 h (n = 3-4, p < 0.05). Since full activation of Akt requires phosphorylation on both serine and threonine residues, these results suggest that Ang-(1-7) significantly reduces Akt activation to inhibit cell growth. Treatment of mice with Ang-(1-7) significantly decreased vessel density in MDA-MB-231 tumors (by 70%), in association with a reduction in the pro-angiogenic factors vascular endothelial growth factor (VEGF, by 72%) and placental growth factor (PlGF, by 58%) [n = 5, p < 0.05]. The heptapeptide caused a concomitant increase in the anti-angiogenic factor sFlt-1, the soluble portion of the VEGF receptor, in triple negative breast cancer cells. Treatment of MDA-MB-231 cells with Ang-(1-7) increased sFlt-1 approximately 7.6-fold, with a maximal effect after 4 h (n = 3-5, p < 0.05). Since sFlt-1 binds VEGF and PlGF but lacks the tyrosine kinase domain, it reduces circulating levels of VEGF and PlGF to attenuate tumor angiogenesis. These results suggest that Ang-(1-7) inhibits tumor cell proliferation and survival as well as angiogenesis and may be a first-in-class targeted treatment for triple negative breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3274. doi:10.1158/1538-7445.AM2011-3274

©2011 American Association for Cancer Research
2011