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Role of HGFL-RON Signaling in Mammary Gland Development and Breast Cancer

Ruiz-Torres, Sasha J.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543920539146247

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Breast cancer is the most common cancer and the second leading cause of cancer-related deaths in women in the United States. Advances in early detection and treatments have improved the outcome of patients with localized/regional disease; however, more than 40,000 patients with aggressive distant breast cancers succumb to this disease each year. This highlights the lack of effectiveness of current treatments in advanced metastatic disease and the need to gain further insight of the mechanisms leading to aggressive breast cancer to develop effective therapies to prevent breast cancer progression and decrease disease mortality. Research on mammary gland development has significantly contributed to understand breast cancer, with cellular processes, cell-to-cell interactions, and pathways important for proper mammary gland development been found deregulated in breast cancer. The RON receptor tyrosine kinase and its ligand HGFL have been recently implicated in breast cancer. However, knowledge of the role of RON and HGFL in regulating mammary gland development and breast cancer progression is limited. Studies presented in this thesis have provided valuable insights that have aided our understanding of the importance and complexity of the HGFL-RON signaling in normal mammary gland development and breast cancer. Studies discussed here have identified novel HGFL-RON-mediated interactions between mammary epithelial cells/tumor cells and cells within the microenvironment that are crucial for proper mammary gland development and breast cancer progression. In addition, studies examining the role of HGFL-RON signaling in mammary gland development provided valuable information about the different cellular compartments where HGFL-RON signaling occurs and led to the studies examining the cell-type specific functions of HGFL-RON signaling in breast cancer progression. Studies discussed in this thesis revealed that activation of HGFL-RON signaling in tumor epithelial cells, breast cancer stem cells, or macrophages promotes breast cancer initiation, progression, and metastasis by supporting tumor cell stemness, proliferation, survival, and migration/invasion as well as by supporting an immunosuppressive microenvironment. Moreover, these studies identified unique tumor promoting activities that are completely dependent on the activation of HGFL-RON signaling on a specific cell-type, such as angiogenesis for epithelial-specific HGFL-RON signaling and M2 macrophage polarization for macrophage-specific HGFL-RON signaling. Furthermore, the studies covered in this thesis identified the respective signaling pathways facilitating the cell-type specific functions of HGFL-RON signaling, with ß-CATENIN and NF-?B mediating breast cancer stem cell maintenance, IL-35 and CXCL13 being potential mediators of the macrophage-specific HGFL-RON phenotypes, and IRAK4, Type I Interferons, and AKT being the major players regulating the epithelial-specific functions of HGFL-RON signaling. Taken together, the studies presented in this thesis have identified HGFL/RON as important regulators of mammary gland development, biomarkers of advanced breast cancer disease, and potential therapeutic targets for the treatment of aggressive breast cancers due to its effects in several RON expressing cell-types, including epithelial tumor cells, breast cancer stem cells, and macrophages, and other immune cells. RON targeting therapies could include the use of RON inhibitors that are currently tested in clinical trials or the development of novel antibody-directed therapeutic strategies against RON.
Susan Waltz, Ph.D. (Committee Chair)
Jun-Lin Guan, Ph.D. (Committee Member)
Simon Hogan, Ph.D. (Committee Member)
Shao-Chun Wang, Ph.D. (Committee Member)
Susanne Wells, Ph.D. (Committee Member)
297 p.
Cellular Biology
HGFL; Breast Cancer Stem Cells; Breast Cancer; RON; Tumor Microenvironment; Mammary Gland Development

Recommended Citations

Citations

  • Ruiz-Torres, S. J. (2018). Role of HGFL-RON Signaling in Mammary Gland Development and Breast Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543920539146247

    APA Style (7th edition)

  • Ruiz-Torres, Sasha. Role of HGFL-RON Signaling in Mammary Gland Development and Breast Cancer. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543920539146247.

    MLA Style (8th edition)

  • Ruiz-Torres, Sasha. "Role of HGFL-RON Signaling in Mammary Gland Development and Breast Cancer." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543920539146247

    Chicago Manual of Style (17th edition)

ucin1543920539146247
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© 2018, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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