Abstract 1633: Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

Abstract Objective of study Cancer associated fibroblasts (CAFs) are often thought to acquire a modified phenotype and these ‘activated’ fibroblasts have been implicated as active partners in tumorigenesis. However, the molecular mechanisms by which CAFs promote tumor progression remain ill-defined. 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 stroma to promote breast cancer progression. The exact mechanisms of how and from where in the stroma Ets2 regulates breast cancer tumorigenesis are poorly understood. The objectives of this study are to determine whether the function of Ets2 in stromal fibroblasts is critical to promote tumor progression and to identify novel tumor-dependent stroma-specific target genes and pathways controlled by Ets2.Our hypothesis is that genetic deletion of Ets2 specifically in the stromal fibroblasts will delay mammary tumor progression. Methods We used Fibroblast specific protein 1 (Fsp1) promoter-Cre to delete Ets2 in the stromal fibroblasts associated with mouse mammary tumors. We evaluated the effect of stromal fibroblast specific deletion of Ets2 on tumor progression and angiogenesis in MMTV-PyMT and MMTV-Her2/neu spontaneous breast cancer mouse models. Also, in order to elucidate the molecular mechanisms by which stromal Ets2 regulates tumor progression, we profiled the primary fibroblasts isolated from mammary glands of mice with Ets2 deletion in the context of both oncogenes. Results We observed a significant delay in tumor progression in both PyMT and Her2/neu tumor models with fibroblast specific Ets2 deletion. Gene expression profiling of fibroblasts from both models revealed that Ets2 in tumor fibroblasts selectively regulated the expression of genes involved in angiogenesis and extracellular matrix (ECM) remodeling. Functional in vivo angiogenesis assays further illustrated a significant decrease in tumor angiogenesis when Ets2 is deleted in fibroblasts. Conclusions Our study demonstrates that stromal fibroblast specific Ets2 drives mammary tumorigenesis by promoting angiogenesis and ECM remodeling. Although the Ets2 deleted fibroblast gene signatures differ between PyMT and Her2/neu models, the study identifies similar pathways affecting tumor angiogenesis in both models. This finding implies a functional role of Ets2 in aiding tumor progression independent of the oncogenic driver. Citation Format: Subhasree Balakrishnan, Julie A. Wallace, Fu Li, Chelsea K. Martin, Thierry Pecot, Gustavo Leone, Michael C. Ostrowski. Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2013-1633