Date of Award

Fall 11-14-2023

Embargo Period

11-14-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Philip H. Howe

Second Advisor

Joseph Delaney

Third Advisor

Jorge Munera

Fourth Advisor

Visu Palanisamy

Fifth Advisor

Lauren Ball

Abstract

The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid-binding protein that plays a tumor-suppressive role in mammary epithelial cells by regulating phenotypic plasticity and cell fate. Following the loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or “ILEI” protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with a poor prognosis. Herein, we characterize a “feed-forward” mechanism that regulates the expression of LIFR in response to FAM3C/LIFR/STAT3 signaling in mammary epithelial cells. We show that the loss of PCBP1 expression upregulates LIFR transcription through activity at the LIFR promoter. We also show that LIFR transcription is affected by modulation of FAM3C expression levels. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with the FAM3C/LIFR interaction and identifies the TWIST1 transcription factor as a downstream effector that participates in the maintenance of LIFR expression. Finally, we characterize the effect of LIFR expression in cell-based experiments using both mouse and human mammary epithelial cells. Our experiments demonstrate the promotion of invasion, migration, and self-renewal of breast cancer stem cells (BCSCs) following increased LIFR expression, which is consistent with previous studies linking LIFR expression to tumor initiation and metastasis in mammary epithelial cells.


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