Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Lynne-Marie Postovit

Abstract

Cancer cell plasticity, whereby stem-cell-like properties are acquired in response to stress, represents a major challenge in cancer treatment. Using cell line and patient-derived xenograft (PDX) models, we demonstrate that translational reprogramming occurs in response to stresses such as hypoxia and chemotherapy which elicits stem cell properties in breast cancer. Other stresses like chemotherapy demonstrate the translational inhibition that has been well characterized as an integral hypoxic cellular response. The inhibition of translation is primarily regulated at initiation by mTOR/4E-BP1 and PERK/eIF2α signalling. We identify previously undescribed 5’ untranslated regions (5’UTRs) of plasticity-associated genes like NANOG, SNAIL and NODAL. A subset of these isoforms facilitates efficient translation during times of stress when global protein synthesis is reduced. We demonstrate that these mRNAs are translationally upregulated by mTOR suppression and concomitant up-regulation in eIF2a phosphorylation, and that translation underpins the reprogramming of breast cancer stem cell (CSC) phenotypes such as self-renewal and epithelial-mesenchymal transition (EMT). Accordingly, we demonstrate that mTOR inhibitors induce stem cell phenotypes in breast cancer, partially explaining their lower-than-expected clinical efficacy. Most notably, we report that stress-induced CSC phenotypes can be overcome with drugs that antagonize the effects of eIF2a phosphorylation and increase ternary complex recycling (e.g. ISRIB). Indeed, studies conducted using cell lines and PDX models indicate that ISRIB decreases CSCs in hypoxic breast tumours and increases the efficacy of mTOR inhibitors and chemotherapies by suppressing breast cancer plasticity.

Available for download on Tuesday, December 31, 2019

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