Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


PhD Thesis_Mary Rose Doherty_2019 .pdf (10.76 MB)

ETD Abstract Container

Abstract Header

INTERFERON-BETA REGULATES CANCER STEM CELL PLASTICITY TO PROMOTE POSITIVE CLINICAL OUTCOME IN TRIPLE-NEGATIVE BREAST CANCER

Doherty, Mary Rose
http://orcid.org/0000-0003-1836-3830
http://rave.ohiolink.edu/etdc/view?acc_num=case1540926583593107

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Pathology.
Triple Negative Breast Cancer (TNBC), the deadliest form of this disease lacks a targeted therapy. Metastasis and tumor recurrence are the primary causes of patient mortality in TNBC and are consistently linked with failure of tumors to respond to standard of care chemotherapy and radiotherapy in the neo-adjuvant, adjuvant and metastatic setting. Accumulating evidence attributes these malignant properties to self-renewing, therapy-resistant Cancer Stem Cells (CSC), which are often enriched in TNBC. Emerging evidence demonstrates that the Tumor Microenvironment (TME) critically influences tumor cell fate by serving as a niche to promote or repress the CSC state by regulating tumor cell differentiation programs. Here, my work begins to explain how TME cytokines such as Oncostatin-M (OSM) and Interferon-beta (IFN-B) oppose one another to regulate tumor cell differentiation and influence clinical outcome in TNBC. I demonstrate that TNBC tumor specimens characterized by elevated IFN-B signaling and Tumor Infiltrating Lymphocytes (TILs) have repressed CSC and improved patient survival. My work demonstrates that IFN-B represses the CSC state by inhibiting tumor cell de-differentiation as evidenced by repressed spontaneous and cytokine-mediated CSC properties in transformed Human Mammary Epithelial Cells (HMEC) and TNBC cell lines. IFN-B repressed expression of the CSC surface marker CD44, inhibited cell motility and tumor sphere formation and repressed expression of critical mesenchymal/CSC transcription factors including SLUG, SNAIL, and VIMENTIN. In contrast to the IFN-B-mediated anti-CSC effect, my work also shows that pro-CSC cytokine OSM represses endogenous IFN-B mRNA and Interferon-Stimulated Genes (ISGs), resulting in acquisition of Mesenchymal/CSC properties including cell motility and enhanced tumor initiation in a pre-clinical TNBC model engineered to express human OSM cDNA. Restoration of IFN-B signaling with treatment of recombinant IFN-B or lentiviral transduction with human IFN-B cDNA repressed OSM-mediated stemness as demonstrated by repressed tumor initiation and Mesenchymal/CSC target proteins like SNAIL. Collectively, this work shows that shifting the balance between pro-CSC cytokine OSM and anti-CSC cytokine IFN-B influences CSC plasticity and tumor cell differentiation status to impact clinical outcomes. This work suggests the therapeutic potential of using IFN-B as a targeted repressor of CSC plasticity for treating and opposing aggressive, spontaneous and OSM-mediated CSC-driven TNBC.
Mark Jackson, Dr/Ph.D (Advisor)
George Stark, Dr/Ph.D (Advisor)
Nicholas Ziat, Dr./Ph.D (Committee Chair)
William Schiemann, Dr./Ph.D (Committee Member)
Justin Lathia, Dr./Ph.D (Committee Member)
Clive Hamlin, Dr./Ph.D (Committee Member)
194 p.
Biomedical Research; Molecular Biology; Oncology; Pathology
Triple Negative Breast Cancer, Interferon-beta, Oncostatin-M, Cancer Stem Cell Plasticity, Tumor Microenvironment

Recommended Citations

Citations

  • Doherty, M. R. (2019). INTERFERON-BETA REGULATES CANCER STEM CELL PLASTICITY TO PROMOTE POSITIVE CLINICAL OUTCOME IN TRIPLE-NEGATIVE BREAST CANCER [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1540926583593107

    APA Style (7th edition)

  • Doherty, Mary. INTERFERON-BETA REGULATES CANCER STEM CELL PLASTICITY TO PROMOTE POSITIVE CLINICAL OUTCOME IN TRIPLE-NEGATIVE BREAST CANCER . 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1540926583593107.

    MLA Style (8th edition)

  • Doherty, Mary. "INTERFERON-BETA REGULATES CANCER STEM CELL PLASTICITY TO PROMOTE POSITIVE CLINICAL OUTCOME IN TRIPLE-NEGATIVE BREAST CANCER ." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1540926583593107

    Chicago Manual of Style (17th edition)

case1540926583593107
198
© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.