Date of Award

2018

Degree Type

Thesis

Degree Name

M.Sc.

Department

Biological Sciences

First Advisor

Porter, Lisa

Keywords

Aldehyde Dehydrogenase; Breast Cancer; Clinical Trial; Spy1; Standard of Care

Rights

CC-BY-NC-ND

Abstract

Triple-negative breast cancer is considered the most aggressive subtype of breast cancer; while patients respond well to initial treatment the tumour relapse rate in patients is approximately 1 in 3. There is increasing evidence for a small population of cells that are able to evade treatment and repopulate the tumour after treatment, called cancer stem cells. Understanding key factors in cancer stem cell resistance is important to decrease tumour relapse. In a Spy1 clinical trial, responses to treatment and in vitro and in vivo to a standard of care treatment are investigated. Spy1 is an atypical cyclin-like regulator that enhances cellular proliferation. Spy1 overexpression has been implicated in cancer stem cell population and drug resistance, in other forms of cancer. The role of Spy1 in resistance to treatment has yet to be elucidated in triple-negative breast cancer (TNBC) cells; however, we have established the knockdown of Spy1 sensitizes cells to treatment. The current standard of care for TNBC is a combination of AC/T. When mimicking clinical treatment in vitro and in vivo, with standard of care with or without carboplatin, a population of cells remain viable after treatment. Detoxification enzymes, like aldehyde dehydrogenase (ALDH), have enhanced expression in cancer stem cell populations; thereby, ALDH can be used as a marker to identify and isolate cancer stem cells. This study outlines the creation and validation of an ALDH reporter system to identify cancer stem cells in heterogeneous triple-negative breast cancer cell lines. Elucidating characteristic of drug-resistant populations, such as expression of Spy1 and ALDH, can provide insight into drug-resistance and tumour relapse.

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