Abstract 5224: Angiotensin-(1-7) inhibits proliferative and fibrotic signaling mechanisms in triple negative breast cancer
Authors: Arter Alison A. , Metheny-Barlow Linda , Gallagher Patricia E. , Tallant E. Ann 
Published: August 2012

Triple negative breast cancer (TNBC), an aggressive and invasive tumor type that accounts for 15% of all breast cancers, disproportionately affects both young, premenopausal women as well as women of African-American and Hispanic descent. TNB tumors display increased activation of both the MAPK and PI3K-Akt proliferative signaling pathways which promote tumor growth and survival. TNB tumors lack estrogen and progesterone receptors and do not over-express the human epidermal growth factor receptor 2 (HER2), severely limiting therapeutic strategies for targeted treatment. Thus, there is a clear need for novel targeted therapies for TNBC patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, seven amino acid peptide hormone of the renin-angiotensin system that activates the G protein-coupled receptor mas. We previously showed that Ang-(1-7) treatment of mice with orthotopic MDA-MB-231 TNB tumors significantly increases the MAPK phosphatase DUSP1 and reduces activation of the MAPKs ERK1 and ERK2 as well as Akt. We now find that incubation of TNBC cells with Ang-(1-7) increases the Akt phosphatase PP2A 3-fold (n=3-4, p&lt;0.01), suggesting that Ang-(1-7) inhibits mitogenic signaling cascades by up-regulating phosphatase activities. The tyrosine kinase Src also contributes to tumor cell survival and motility in TNBC, and Ang-(1-7) reduces phosphorylation of Src (Tyr416) by 40% (n=3, p&lt;0.01) in MDA-MB-231 cells, suggesting that the heptapeptide disrupts Src signaling to prevent TNB tumor progression. Tumor progression is also regulated by stromal fibroblasts in the tumor microenvironment which produce growth factors and extracellular matrix (ECM) proteins, contributing to the proliferation and stabilization of the tumor. Ang-(1-7) increases DUSP1 2.5-fold (n=3, p&lt;0.05) in cancer-associated fibroblasts (CAF) isolated from orthotopic 4T1 TNB tumors with a concomitant decrease in phospho-ERK1/2, demonstrating that the heptapeptide also reduces proliferative signaling pathways in CAFs to prevent tumor growth. Transforming growth factor-β (TGF-β) participates in the transformation of tumor-promoting CAFs by phosphorylation of Smad2/3 which translocates to the nucleus to induce pro-fibrotic gene expression. TGF-β stimulation of CAFs isolated from 4T1 tumors increases phospho-Smad2/3 which was significantly reduced by pre-treatment with Ang-(1-7), suggesting that the heptapeptide inhibits both the growth of stromal fibroblasts as well as the signaling pathways that participate in ECM protein production. These results demonstrate that Ang-(1-7) inhibits TNB tumor growth by direct effects on the tumor cells to reduce proliferation and survival as well as attenuating the proliferative and pro-fibrotic effects of stromal fibroblasts in the tumor microenvironment, suggesting that the heptapeptide may serve as a novel, pleiotropic therapy for TNBC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5224. doi:1538-7445.AM2012-5224