Triple negative breast tumors are an aggressive form of breast cancer that predominantly affects young African-American and Hispanic women with lower socio-economic status. This form of breast cancer is correlated with a poor survival rate regardless of stage at diagnosis due to development of distant metastases. Triple negative tumors lack estrogen and progesterone receptors and have normal expression of the human epidermal growth factor receptor HER2 (ERBB2), severely limiting the therapeutic strategy for treatment. The purpose of this study was to determine whether angiotensin-(1-7) [Ang-(1-7)], an endogenous peptide hormone that activates the AT(1-7) receptor mas, can be used as a targeted chemotherapeutic agent in the treatment of triple negative breast cancer. Ang-(1-7) significantly inhibited the growth of MDA-MB-231 cells, a triple negative breast cancer cell line. More importantly, the heptapeptide significantly reduced the proliferation of human triple negative breast tumor growth in vivo, using an orthotopic model. Athymic mice with tumors resulting from injection of human MDA-MB-231 cells in the mammary fat pads were treated for 28 days with either saline or 1000 μg/kg Ang-(1-7), delivered by subcutaneous injection every 12 h. The average volume of the tumors from mice treated with the heptapeptide was approximately 3-fold less than the size of the tumors from control animals (170.8 ± 21.4 mm3 versus 546.7 ± 87.9 mm3; n = 5, p < 0.05). In addition, Ang-(1-7) administration markedly reduced tumor weight, from 1.0 ± 0.2 g in the saline-treated mice to 0.5 ± 0.1 g in Ang-(1-7)-treated mice (n = 5, p<0.05). The decrease in tumor growth of Ang-(1-7)-treated mice was associated with a significant reduction in immunoreactive Ki67, a proliferation marker (from 84.2% ± 8.2 to 41% ± 7.6, p < 0.05). The mitogen-activated protein (MAP) kinase ERK2 also was reduced in tumors from Ang-(1-7)-treated mice (2.0 ± to 0.5 densitometric units to 0.7 ± 0.2 densitometric units, p < 0.05), in association with an increase in MAP kinase phosphatase DUSP-1 mRNA (1.01 ± 0.1 relative gene expression in tumors from saline-treated mice to 1.78 ± 0.13 in tumors from Ang-(1-7)-treated mice), suggesting that Ang-(1-7) up-regulates DUSP-1. This suggests that Ang-(1-7) transcriptionally up-regulates DUSP-1 to prevent MAP kinase activation, thereby reducing cell proliferation and tumor growth. Tumors treated with Ang-(1-7) also showed a decrease in the endothelial cell marker CD34 (87.8 ± 6.4 to 32.0 ± 7.0, p < 0.05), demonstrating that the observed reduction in tumor growth was due, in part, to inhibition of angiogenesis. Based on the anti-proliferative and anti-angiogenic properties of the heptapeptide, Ang-(1-7) may be a new, first-in-class compound for the treatment of triple negative breast tumors targeting a specific AT(1-7) receptor mas.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA