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

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