We have discovered a critical tumor suppressor function for Pten in stromal fibroblasts during mammary tumor progression. Consequences of Pten/Ets2 pathway disruption in stromal fibroblasts in the MMTV-ErbB2 mammary tumor model include massive remodeling of the EGM and its constituents, increased inflammation and increased angiogenesis. Importantly, the Pten disruption signature can be found in human tumor stroma and can predict patient outcome. In collaboration with Project 3, we have recently found that the Pten signature is enriched in breast tumor stromal subclasses associated with non-luminal breast cancer and poor patient outcome. Based on these findings, our overall hypothesis is that defining the tumor microenvironment (TME) pathways activated by Pten loss in stromal fibroblasts will uncover the mechanisms of co-evolution of mammary tumor and stroma, findings that can be translated directly to human breast cancer. The proposal has three Aims:
AIM 1 : Identify gene expression networks regulated by Pten in the tumor microenvironment. Specific hypothesis to be tested: The differential effect of stromal Pten loss on the ErbB2 model is due to the activation of a specific pathway(s) that complements ErbB2 function. Expected Outcome: Networks that control cross-talk between different cell compartments in the TME and that correlate with patient outcome will be identified.
AIM 2 : Determine mechanisms by which stromal Pten pathways contribute to tumor progression. Specific Hypothesis to be tested: miR-320 is one Pten effector that controls epithelial cell migration and growth, as well as endothelial migration and/or proliferation, coupling tumor invasiveness and angiogenesis. Expected Outcome: We will experimentally verify the critical Pten pathways in the TME, and uncover the mechanisms involved.
Aim 3 : Use experimentally verified Pten-dependent TME networks to identify potential biomarkers for predicting outcome and selecting treatment strategies for human breast cancer. Specific Hypothesis to be tested: Stromal biomarkers present in multiple tumor microenvironment cell compartments will be useful in stratifying breast cancer patients and predicting patient outcome. Expected Outcome: We will reveal the pathways in the mouse models that are most relevant to human breast cancer, and begin testing their role as potential biomarkers for breast cancer subclasses.

Public Health Relevance

Breast cancer remains the second leading cause of cancer death in women, with 40,000 deaths in the US, and over 500,000 deaths worldwide, in 2010 alone. This project focuses on how the stroma of breast tumors promotes growth and spread of breast cancer. If successful, our studies will provide a significant advance in our basic knowledge of tumor-stroma interactions, and provide the tools to better stratify breast cancer patients so that treatments can be tailored to individual patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA097189-06
Application #
8246040
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Project Start
2011-12-01
Project End
2017-05-31
Budget Start
2012-06-21
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$301,069
Indirect Cost
$67,221
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
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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
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
Kent, Lindsey N; Bae, Sooin; Tsai, Shih-Yin et al. (2017) Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest 127:830-842
Wu, Jinghai; Liu, Xin; Nayak, Sunayana G et al. (2017) Generation of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele. PLoS One 12:e0184984
Sizemore, Gina M; Pitarresi, Jason R; Balakrishnan, Subhasree et al. (2017) The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer 17:337-351
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

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