Author ORCID Identifier
https://orcid.org/0000-0002-2904-5582
Date of Graduation
8-2021
Document Type
Thesis (MS)
Program Affiliation
Genetics and Epigenetics
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Wenbo Li, Ph.D
Committee Member
Jeffrey M Rosen, Ph.D.
Committee Member
Ambro van Hoof, Ph.D.
Committee Member
Juan Fueyo, M.D., F.A.A.N
Committee Member
Leng Han, Ph.D.
Abstract
In the U.S., the highest number of new cancer cases belongs to breast cancer in women, and this cancer also bears the second-highest death rate in women. Despite significant progress in breast cancer treatment that has been made in the past several decades, innovative and efficient therapies are still needed to eradicate this deadly disease. Novel cancer immunotherapy with immune checkpoint blockade (ICB) could induce long-lasting responses and improve survival in hard-to-treat malignancies. Regrettably, only a fraction of breast cancer patients respond to this highly promising strategy. To improving ICB therapy in breast cancer treatment, IFN signaling induction is a potential approach. Our results demonstrated that depletion of several RNA-binding proteins, particularly a poorly known ARGLU1, triggered type I interferon signaling in breast cancer cells. This phenomenon was also seen in mouse breast cancer cells but was not seen in normal breast epithelial cells. Furthermore, my results suggested that the loss of ARGLU1 induced accumulation of dsRNAs, which were recognized by dsRNA sensors such as RIG-I and MDA5, leading to augmented IFN signaling. To identify RNAs directly bound by ARGLU1, Halotag-fused ARGLU1 was expressed in MCF7 cells for conducting CLIP-seq. These results elucidate unappreciated regulators of type I IFN signaling in breast cancer, offering potentially new targets to overcome cancer resistance to immune checkpoint blockade therapy.
Keywords
breast cancer, ARGLU1, immune checkpoint blockade, IFN, RNA-binding proteins, dsRNA, RIG-I, MDA5, Halotag
Included in
Genetics Commons, Medicine and Health Sciences Commons, Molecular Biology Commons, Molecular Genetics Commons