Author ORCID Identifier

https://orcid.org/0000-0002-6768-9338

Year of Publication

2019

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Molecular and Cellular Biochemistry

First Advisor

Dr. Binhua P. Zhou

Abstract

RBMS3 belongs to the family of c-myc gene single-strand binding proteins (MSSPs) that play important roles in transcriptional regulation. Here, we show that RBMS3 functions as a tumor promoter in triple-negative breast cancer (TNBC), a highly aggressive BC subtype. Analysis of RBMS3 expression shows that RBMS3 is upregulated at both mRNA and protein levels in TNBC cells. Functionally, overexpression of RBMS3 increases cell migration, invasion and cancer stem cell (CSC) behaviors. Moreover, RBMS3 induces expression of epithelial-mesenchymal transition (EMT) and CSC markers. Conversely, loss of RBMS3 in TNBC BT549 cells inhibits cell proliferation, migration and mesenchymal phenotype. Correlation analysis shows RBMS3 is associated with TGF-β signaling. Mechanistically, RBMS3 interacts with Smad2, Smad3 and Smad4 mRNA and regulates the stability of these transcripts. Importantly, RBMS3 prevents TGF-β-induced cytostasis and apoptosis in premalignant cancer cells. Moreover, RBMS3 inversely correlates with expression of ESRPs, epithelial-specific splicing regulatory proteins that regulate morphogenesis-associated alternative splicing events. ESRPs appear to suppress EMT through distinct mechanisms: ESRP1 restricted cell migration, whereas ESRP2 prevented cell growth. RBMS3 significantly facilitates the EMT process when ESRPs are lost. Collectively, the studies within this dissertation identify RBMS3 as a positive regulator of EMT and breast cancer progression by regulating the TGF-β signaling pathway.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2019.433

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