Faculty Collaboration Database

Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer. PLoS One 2013;8(8):e71533

Date

08/27/2013

Pubmed ID

23977064

Pubmed Central ID

PMC3745457

DOI

10.1371/journal.pone.0071533

Scopus ID

2-s2.0-84881561093 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

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.

Author List

Wallace JA, Li F, Balakrishnan S, Cantemir-Stone CZ, Pecot T, Martin C, Kladney RD, Sharma SM, Trimboli AJ, Fernandez SA, Yu L, Rosol TJ, Stromberg PC, Lesurf R, Hallett M, Park M, Leone G, Ostrowski MC

Author

Anthony J. Trimboli PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Carcinogenesis
Cell Compartmentation
Disease Models, Animal
Disease Progression
Female
Fibroblasts
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Mammary Neoplasms, Animal
Mice
Proto-Oncogene Protein c-ets-2
Stromal Cells
Treatment Outcome