Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer

• Published in: PloS one 2013-08, Vol.8 (8), p.e71533
• Main Authors: Wallace, Julie A, Li, Fu, Balakrishnan, Subhasree, Cantemir-Stone, Carmen Z, Pecot, Thierry, Martin, Chelsea, Kladney, Raleigh D, Sharma, Sudarshana M, Trimboli, Anthony J, Fernandez, Soledad A, Yu, Lianbo, Rosol, Thomas J, Stromberg, Paul C, Lesurf, Robert, Hallett, Michael, Park, Morag, Leone, Gustavo, Ostrowski, Michael C
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Biochemistry; Biology; Blood; Blood vessels; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer therapies; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Compartmentation; Cell migration; Clonal deletion; Deactivation; Development and progression; Disease Models, Animal; Disease Progression; Endothelial cells; Epithelial cells; ErbB-2 protein; Ets-2 protein; Extracellular matrix; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetics; Humans; Immunology; Inactivation; Kinases; Mammary gland; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Medical prognosis; Medicine; Metastasis; Mice; Neovascularization; Prostate; Proto-Oncogene Protein c-ets-2 - metabolism; Rodents; Signaling; Stem cells; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; Treatment Outcome; Tumor cells; Tumors; Veterinary colleges; Veterinary medicine; Virology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0071533

Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.