All ETDs from UAB

Advisory Committee Chair

Rajeev Samant

Advisory Committee Members

Susan Bellis

Stuart Frank

Lalita Shevde-Samant

Eddy Shih-Hsin Yang

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Previously, abnormal nucleoli were noted as indicators of cancerous lesions andused as a pathologic readout of neoplasia. Nucleolar hypertrophy and increased nucleolar number have been correlated with increased breast cancer (BC) mortality rates. Although various functions of the nucleolus have been investigated, it remains widely understudied in the context of cancer. The nucleolus was initially thought to be solely the site of ribosome biogenesis. However, over half of the proteins found in the nucleolus are associated with other biological functions. It is evident that the nucleolus plays major roles in stress response, DNA repair, and critical cellular aspects that influence cancer progression. BC is one of the most common types of cancer in women. One key signaling pathway known to regulate tumor growth, metabolic adaptation, and cellular stress response in BC is Wnt signaling. BC patients with upregulated Wnt signaling often have poor clinical prognoses. However, the effects of Wnt/β-catenin signaling on the nucleolus and the resultant impact on cancer development and progression remain unclear. Studies in our lab revealed that triple negative breast cancer (TNBC) patient tissue has significantly higher nucleolar staining than non-TNBC tissue samples, a trend also iv observed in TNBC cell lines compared to non-TNBC cell lines. Our comparative proteomic analysis revealed several changes in the composition of the nucleolar proteome of TNBC cells compared to Non TNBC cells. The majority of proteins enriched in the nucleoli of TNBC cells were potential targets of Wnt/β-catenin signaling. Upon inhibition of Wnt/β-catenin signaling, we observed a notable reduction in the number of nucleoli per nucleus in TNBC cell lines. Our comparative proteomic analysis revealed several changes in the composition of the nucleolar proteome of TNBC cells upon inhibition of Wnt/β-catenin signaling. We identified the nucleolar protein LAS1L was significantly more abundant in TNBC cells and significantly reduced after inhibition of βcatenin signaling. We demonstrated that LAS1L promotes invasive progression of BC. Overall, we posit that Wnt/β-catenin signaling affects nucleolar functionality and thus influence BC progression. Understanding the role of Wnt signaling in the nucleolus and BC is a critical step towards developing novel therapeutic options for BC treatment.

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