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David Taffany PhD Dissertation.pdf (44.1 MB)

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Ets2 and PU.1 Cooperatively Regulate Key Oncogenic Pathways in Tumor-Associated Macrophages

Taffany, David Austin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1409014508

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Despite recently declining rates of incidence and mortality, breast cancer remains the second leading cause of cancer death in American women. Much of the difficulty in treating this disease stems from the extreme diversity of cell types that compose the mammalian breast and the complexity of communication among them. Recently, macrophages and cells of the myeloid lineage have been discovered as key mediators of tumor progression, yet the precise mechanism through which this occurs remains relatively unsolved. The answer may lie in studying the ETS family of transcription factors, known to regulate many genes in cancer-relevant cell processes such as growth, proliferation, and motility. Ets2 in particular has been an attractive target as previous research suggests it has stroma-specific oncogenic potential. Through transgenic mouse tumor models, here we show that disabling Ets2 specifically within tumor-associated macrophages results in stunted tumor growth at both the primary and metastatic sites. Gene expression profiling and chromatin immunoprecipitation experiments reveal Ets2 directly binds and represses key anti-angiogenic genes, resulting in reduced tumor vasculature, thus limiting breast tumor growth and spread. Furthermore, PU.1, an ETS family member with wide influence over the cells of the hematopoietic lineage, was found to collaborate with Ets2 to regulate expression of key oncogenes Hif1a and IL-6. These results reveal that ETS factors work together as master regulators to influence angiogenesis and inflammation from within the macrophage compartment. These findings have implications for novel breast cancer therapies and prognostic tools. Macrophage-specific Ets2 deletion resulted in dysregulation of hundreds of genes. Comparing these genes with human breast cancer patient datasets resulted in a novel gene signature capable of retroactively predicting patient survival in multiple breast cancer subtypes including the highly aggressive ER-negative classification. Thus, the ETS family members Ets2 and PU.1 act cooperatively to regulate key oncogenic pathways in tumor-associated macrophages, thereby exhibiting stromal-specific regulation of tumor growth and metastasis.
Michael Ostrowski, PhD (Advisor)
Gustavo Leone, PhD (Committee Member)
Thomas Ludwig, PhD (Committee Member)
Qianben Wang, PhD (Committee Member)
245 p.
Biology; Biomedical Research; Cellular Biology; Genetics; Health; Molecular Biology; Oncology
breast cancer; metastasis; ets; ets2; pu1; macrophages; tumor-associated macrophages;

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Citations

  • Taffany, D. A. (2014). Ets2 and PU.1 Cooperatively Regulate Key Oncogenic Pathways in Tumor-Associated Macrophages [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1409014508

    APA Style (7th edition)

  • Taffany, David. Ets2 and PU.1 Cooperatively Regulate Key Oncogenic Pathways in Tumor-Associated Macrophages. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1409014508.

    MLA Style (8th edition)

  • Taffany, David. "Ets2 and PU.1 Cooperatively Regulate Key Oncogenic Pathways in Tumor-Associated Macrophages." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1409014508

    Chicago Manual of Style (17th edition)

osu1409014508
94
© 2014, some rights reserved.Creative Commons License Ets2 and PU.1 Cooperatively Regulate Key Oncogenic Pathways in Tumor-Associated Macrophages by David Austin Taffany is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.
Release 3.2.12