Date of Award

12-6-2019

Publication Type

Doctoral Thesis

Degree Name

Ph.D.

Department

Biological Sciences

Keywords

Breast Cancer, Chemotherapeutics, Drug Toxicity, Immune system, Zebrafish xenograft

Supervisor

Lisa Porter

Rights

info:eu-repo/semantics/embargoedAccess

Abstract

Though modern medicine has greatly improved detection and treatment of breast cancer and overall survival rates are around 85%, this disease is still the second most fatal cancer in Canada. Once the cancer becomes metastatic, it is considered incurable and treatment strategies are directed towards maintenance of the disease rather than curing it. Another hurdle to breast cancer treatment is the severity of side effects from chemotherapeutics, for example cardiotoxicity and hepatotoxicity, that are sometimes fatal. Dexamethasone (Dex) is a synthetic glucocorticoid (GC) that has been shown to be effective at reducing the less severe side effects of chemotherapeutics, such as nausea and inflammation. There is growing concern that Dex interferes with the effectiveness of anti-cancer drugs because of chronic suppression of the immune system, which has been implicated in cancer progression in some inflammatory diseases. The use of natural health products (NHPs) to treat inflammation is a growing field of research to find alternatives to synthetic GCs and many are already on the market. To study the toxicity of drug combinations there needs to be an efficient model that accurately incorporates immune response and organ toxicity. Zebrafish have become an increasingly used animal model to study human cancer and drug toxicity because they are cost effective and can be used for high throughput assays. Using a zebrafish model optimized for this work, we show that Dex increases the metastatic potential of breast cancer cells and accentuates the cardiotoxicity and hepatotoxicity of embryos when treated in combination with cyclophosphamide but not with paclitaxel. We also show that the NHP, Nutria plus, has anti-inflammatory and antioxidant properties and may be a beneficial supplement for treating inflammatory diseases and preventing cancer drug toxicity. Together these results show that the ubiquitous use of Dex in clinics should be re-evaluated. We also studied cell cycle regulation of mammary acini development and cancer metastasis. We show, for the first time, that increased expression of the cell cycle regulator, Spy1, leads to multi-acinar mammary alveolar structures in vitro, and leads to increased metastasis of breast cells in an in vivo zebrafish model, introducing Spy1 as a potential target for treatment of metastatic breast cancer.

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