title: Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.
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.
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: Julie A
authors: JA
authors: Wallace
authors: Fu
authors: F
authors: Li
authors: Subhasree
authors: S
authors: Balakrishnan
authors: Carmen Z
authors: CZ
authors: Cantemir-Stone
authors: Thierry
authors: T
authors: Pecot
authors: Chelsea
authors: C
authors: Martin
authors: Raleigh D
authors: RD
authors: Kladney
authors: Sudarshana M
authors: SM
authors: Sharma
authors: Anthony J
authors: AJ
authors: Trimboli
authors: Soledad A
authors: SA
authors: Fernandez
authors: Lianbo
authors: L
authors: Yu
authors: Thomas J
authors: TJ
authors: Rosol
authors: Paul C
authors: PC
authors: Stromberg
authors: Robert
authors: R
authors: Lesurf
authors: Michael
authors: M
authors: Hallett
authors: Morag
authors: M
authors: Park
authors: Gustavo
authors: G
authors: Leone
authors: Michael C
authors: MC
authors: Ostrowski
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002451:Cell Compartmentation; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D051379:Mice; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: C494069:ETS2 protein, human; C494070:Ets2 protein, mouse; D050787:Proto-Oncogene Protein c-ets-2
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