Poster abstracts

Poster number 56 submitted by Subhasree Balakrishnan

Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer

Subhasee Balakrishnan (Molecular and Cellular Biochemistry, College of Medicine), Julie Wallace (Molecular and Cellular Biochemistry, College of Medicine), Fu Li (Department of Molecular Genetics), Chelsea Martin (Department of Molecular Virology, Immunology and Medical Genetics), Thierry Pecot (Solid Tumor Biology Program, Comprehensive Cancer Center), Anthony J Trimboli (Solid Tumor Biology Program, Comprehensive Cancer Center)

Abstract:
Ets2 (v-ets erythroblastosis virus E26 oncogene homologue 2) is an evolutionarily conserved proto-oncogene overexpressed in breast cancer. Previous studies indicate that Ets2 specifically acts in the tumor microenvironment to promote breast cancer progression. The exact mechanisms of how and from where in the stroma Ets2 regulates breast cancer are poorly understood. We hypothesized that genetic deletion of Ets2 in the stromal fibroblasts will delay mammary tumor progression. Our goals were to determine the role stromal fibroblast Ets2 in mediating breast tumorigenesis and to identify stroma-specific target genes and pathways regulated by Ets2. We used fibroblast specific Fsp-Cre and epithelial specific MMTV-Cre to delete Ets2 in the fibroblasts and epithelial cells respectively in PyMT breast cancer model. We also evaluated the effect deleting fibroblast Ets2 in MMTV-ErbB2 oncogene driven breast tumors. To dissect out changes in molecular pathways, we carried out gene expression profiling experiments on primary fibroblasts isolated from both tumor models. Ablation of fibroblast Ets2 in both PyMT and ErbB2 models caused a significant decrease in tumor growth. Gene expression profiling of fibroblasts revealed a tumor- and Ets2- specific gene signature enriched for genes involved in angiogenesis and ECM remodeling. Functional in vivo angiogenesis assays in both tumor models further illustrated a significant decrease in tumor angiogenesis when Ets2 is deleted in fibroblasts. Importantly, the Ets2-dependent gene expression signatures were able to distinguish microdissected human breast tumor stroma from normal stroma, and correlated with patient outcomes in whole tumor breast cancer datasets. Our study demonstrates that fibroblast specific Ets2 drives mammary tumorigenesis by promoting tumor angiogenesis and that targeting tumor fibroblasts could pave the way for identifying novel anti-angiogenic therapies.

Keywords: Ets2, angiogenesis, fibroblasts