Defense Date


Document Type


Degree Name

Master of Science


Molecular Biology and Genetics

First Advisor

Masoud Manjili


The successful treatment of breast cancer is limited due to a fraction of tumor cells escaping drug-treatment by entering a dormant state, only to relapse years or decades later at distant sites. Host-driven chronic inflammatory cells such as M2 macrophages play an important role in tumorigenesis, but the role of tumor-intrinsic inflammatory signaling involved in tumor dormancy and recurrence is unknown. We sought to determine the role of tumor-intrinsic inflammatory pathways in mouse mammary carcinoma cells (MMC) treated with Adriamycin (ADR), a clinically relevant chemotherapeutic drug. We found that ADR-induced dormant tumor cells autonomously produced pro-inflammatory cytokines, in vitro. MMC treated with Chloroquine (CQ) prior to ADR treatment displayed a delay in relapse, or prolonging of dormancy, when compared to ADR-treated MMC. Additional gene array data showed predicated activation of NF-κB p65 in ADR-treated dormant MMC that eventually relapsed. These data suggest that the anti-inflammatory function of CQ led to prolonged dormancy. To test this, we investigated the role of inflammatory signaling pathways directly by shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout of NF-κB p65 in MMC. We found that knockdown of NF-κB p65 resulted in fewer dormant cells after ADR treatment and reduced rate of relapse, in vitro. NF-κB p65 was also found to reduce the immunomodulatory effects of ADR, with shNF-κB p65 showing increased upregulation of neu upon ADR treatment. Additionally, we found NF-κB p65 to be associated with a higher infiltration of CD8+ T cells and anti-tumor T cell responses. Our findings suggest a dual role of tumor-intrinsic NF-κB p65 pathway, allowing for escape from drug treatment through dormancy which leads to relapse, but also for proper lymphocyte infiltration and subsequent anti-tumor activity.


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