Abstract 1011: Metformin inhibits angiogenesis, local and metastatic growth of triple-negative breast cancer by targeting two classes of adipose tissue progenitors

Abstract

Abstract We have recently reported that human white adipose tissue (WAT) contains two classes of CD45-CD34+ progenitors with cooperative roles in triple negative breast cancer progression. In orthotopic murine models we found that 1) purified human WAT CD34+CD13+ mesenchymal adipose stromal cell progenitors (ASCs) were not able to migrate but promoted local tumor growth in the mammary fat pad and 2) purified human WAT CD34+CD31+ endothelial progenitors (EPCs) were able to migrate towards lymph nodes and blood and promoted breast cancer cell EMT, migration, invasion and metastatic growth (Orecchioni et al, 2013). Here we report that in several in vitro and in vivo models the biguanide Metformin, a drug commonly used in type 2 diabetes management, is able to inhibit angiogenesis, local and metastatic growth of triple negative breast cancer by targeting WAT progenitors. First, we and others (Dallaglio et al, in press) have found in collaborative studies that Metformin inhibits the formation of capillary-like networks by HUVEC cells. This effect was partially AMPK-dependent. Metformin inhibited VEGF-dependent activation of ERK1/2, angiogenesis in matrigel pellets in vivo, and decreased microvessel density in tumor-free mice. The effect of Metformin on WAT progenitors was then studied in vivo in several immune-competent and immune-deficient murine strains with and without triple negative breast cancer. In immune-competent mice, low-dose Metformin (2mg/mL drinking water) induced apoptosis and increased hypoxia of CD34+CD31+ WAT EPCs. As a result of low-dose Metformin administration, WAT and cancer vessels were quantitatively reduced, had a significant impairment of the pericyte/endothelial cell ratio and displayed a branching and dysplastic phenotype. This effect was also observed in immune-competent mice on high fat diet receiving Metformin. WAT CD34+ ASC were targeted by higher doses of Metformin, which were associated with a reduced pericyte coverage of new blood vessels. As Metformin is frequently administered along with aspirin and beta-blockers in diabetic and obese patients, we studied in vivo the association of these three drugs in murine models of triple negative breast cancer. In several immune-deficient murine models, the beta-blocker Atenolol significantly synergized with Metformin in inhibiting both local and metastatic breast cancer growth. In immune-competent murine strains, the anti-metastatic effect of Metformin and Atenolol was further enhanced by the addition of aspirin. These effects were observed in several murine models generated by both p53 mutated or p53 wild type triple negative breast cancer cells. We are currently investigating the molecular mechanisms used by Metformin to inhibit WAT progenitors and the most efficient schedules of administration of Metformin, Atenolol and Aspirin to target local and metastatic breast cancer growth. Citation Format: Stefania Orecchioni, Giuliana Gregato, Francesca Reggiani, Patrizia Mancuso, Angelica Calleri, Giovanna Talarico, Valentina Labanca, Francesco Bertolini. Metformin inhibits angiogenesis, local and metastatic growth of triple-negative breast cancer by targeting two classes of adipose tissue progenitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1011. doi:10.1158/1538-7445.AM2014-1011