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Alex Gooding ETD.pdf (6.54 MB)

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Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis

Gooding, Alex Joseph
http://orcid.org/0000-0001-6331-5710
http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pathology.
Breast cancer is the most common malignancy and second most common cause of cancer-related death in women, a clinical challenge exasperated by the lack of targeted therapies for metastasis, the most deadly component of breast cancer. Although the molecular mechanisms underpinning the dissemination of primary breast cancer cells to distant tissues remain incompletely understood, long noncoding RNAs (lncRNAs) have emerged as potent regulators of breast cancer development and progression, including the metastatic spread of disease. Through in silico and biological analyses, we identified a novel lncRNA, BMP/OP-Responsive Gene (BORG), whose expression directly correlates with aggressive breast cancer phenotypes, as well as with metastatic competence and disease recurrence in multiple clinical breast cancer patient cohorts. Mechanistically, BORG elicits the metastatic outgrowth of latent breast cancer cells by promoting the localization and transcriptional repressive activity of TRIM28, which binds BORG and induces substantial alterations in carcinoma proliferation and survival. Moreover, inhibiting BORG expression in metastatic breast cancer cells impedes their metastatic colonization of the lungs of mice, implying that BORG acts as a novel driver of the genetic and epigenetic alterations that underlie the acquisition of metastatic and recurrent phenotypes by breast cancer cells. Interestingly, the BORG-dependent transcriptome demonstrates enhanced signaling through survival and viability pathways, as well as decreased activation of cell death pathways. Accordingly, we determined that BORG expression is broadly promoted by environmental and chemotherapeutic stresses, a transcriptional response that facilitates the survival of breast cancer cells. These effects rely upon a BORG-induced induction of NF- B signaling as part of a feed-forward NF- B signaling loop, as well as its ability to bind and activate RPA1. Taken together, our mechanistic insights into BORG-mediated metastasis and chemoresistance offer the foundation necessary to develop therapies that target the molecular drivers vital to metastatic outgrowth of disseminated breast cancer cells, particularly those persisting in a dormant state.
William Schiemann (Advisor)
Hannah Gilmore (Committee Chair)
Saba Valadkhan (Committee Member)
Mark Jackson (Committee Member)
Goutham Narla (Committee Member)
261 p.
Oncology; Pathology
Breast cancer, lncRNAs, metastasis, metastatic latency, chemoresistance

Recommended Citations

Citations

  • Gooding, A. J. (2018). Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762

    APA Style (7th edition)

  • Gooding, Alex. Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762.

    MLA Style (8th edition)

  • Gooding, Alex. "Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762

    Chicago Manual of Style (17th edition)

case1528462540265762
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© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.