A substantial body of evidence indicates that ras signaling pathways play a role in multi-stage progression of human breast cancer, even though the mechanisms of activation of these pathways does not usually include activating mutations in the ras genes. We have identified ets-2 as a nuclear target of ras pathways that can persistently activate gene expression, and more recently have demonstrated that ets-2 can also repress gene expression in a signaling-dependent fashion. Gene targets include members of the EGF ligand family, such as HB-EGF, as well as a group of extracellular proteases including urokinase plasminogen activator, stromelysin 1/MMP3, MMP9 and MMP-MT1. The identity of these target genes suggests that the ras/ets-2 pathway may be activated during the epithelial-mesenchymal transition that occurs in the tumor cell and coincides with a more metastatic phenotype. However, these target genes are also expressed in other types of cells in the tumor microenvironment during tumor progression, particularly in macrophages and stromal fibroblasts. This leads to the proposition that the ras/ets-2 pathway may be activated in several cell types in the tumor microenvironment and may play distinct roles in different stages of tumor progression. We propose to use conditional gene knockout approaches to remove ets-2 in macrophages and stromal fibroblasts in the mammary tumor microenvironment. We also propose to develop orthotopic mouse models that will allow us to study the role of ets-2 stromal fibroblasts during tumor metastasis. In combination with the other two Projects in this Program Project Grant, we will also study interactions between the ras/ets-2, Pten and Rb/E2F pathways. These experiments will give us a better understanding of the role of the ras/ets-2 pathway in coordinating expression of genes in a temporal and spatial specific pattern during mammary tumor progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097189-02
Application #
7120663
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$185,073
Indirect Cost
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Rudolph, M; Sizemore, S T; Lu, Y et al. (2018) A hedgehog pathway-dependent gene signature is associated with poor clinical outcomes in Luminal A breast cancer. Breast Cancer Res Treat 169:457-467
Sizemore, Gina M; Balakrishnan, Subhasree; Thies, Katie A et al. (2018) Stromal PTEN determines mammary epithelial response to radiotherapy. Nat Commun 9:2783
Sizemore, Steven T; Mohammad, Rahman; Sizemore, Gina M et al. (2018) Synthetic Lethality of PARP Inhibition and Ionizing Radiation is p53-dependent. Mol Cancer Res 16:1092-1102
Pitarresi, Jason R; Liu, Xin; Avendano, Alex et al. (2018) Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth. Life Sci Alliance 1:e201800190
Ahirwar, Dinesh K; Nasser, Mohd W; Ouseph, Madhu M et al. (2018) Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. Oncogene 37:4428-4442
Victor, Aaron R; Nalin, Ansel P; Dong, Wenjuan et al. (2017) IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-?B. J Immunol 199:2333-2342
Liu, Huayang; Dowdle, James A; Khurshid, Safiya et al. (2017) Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation. Dev Cell 41:392-407.e6
Tang, Xing; Srivastava, Arunima; Liu, Huayang et al. (2017) annoPeak: a web application to annotate and visualize peaks from ChIP-seq/ChIP-exo-seq. Bioinformatics 33:1570-1571
Sizemore, G M; Balakrishnan, S; Hammer, A M et al. (2017) Stromal PTEN inhibits the expansion of mammary epithelial stem cells through Jagged-1. Oncogene 36:2297-2308
Hammer, Anisha M; Sizemore, Gina M; Shukla, Vasudha C et al. (2017) Stromal PDGFR-? Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth. Neoplasia 19:496-508

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