Date of Award

2014

Publication Type

Doctoral Thesis

Degree Name

Ph.D.

Department

Biological Sciences

Keywords

Breast Cancer, Dexamethasone, Glucocorticoids, Metastasis, Paclitaxel

Supervisor

Porter, Lisa

Rights

info:eu-repo/semantics/openAccess

Abstract

Endogenous glucocorticoid (GC) steroids are lipophilic hormones secreted in response to the hypothalamic-pituitary-adrenal axis. Their anti-inflammatory and immunosuppressive potency is the basis for their frequent use in clinical applications. Dexamethasone (Dex) is a synthetic GC given to breast cancer patients to reduce emetic effects of chemotherapeutic drugs (e.g., paclitaxel (Pac)). GCs mediate their effects on cell behaviour through activation of the GC receptor (GR). Active GR regulates approximately 10% of the human genome influencing numerous physiological and developmental parameters including cell proliferation, invasion, migration, and survival. The prevalent use of Dex in breast cancer treatment is disconcerting given that little is known about its impact on breast cancer cell behaviour. We show that Dex can increase the ability of triple negative breast cancer cells to survive, migrate and invade in vitro as well as enhance overall metastatic properties (e.g., survival, and/or motility) in vivo. Moreover, there is growing evidence that the ability of Dex to promote survival extends to protection from chemotherapy-induced cell death. We show that Dex protects triple negative and luminal breast cancer cells from Pac-induced apoptosis through contrary regulation of nuclear factor kappa B (NFkB) activity. We show that Pac-activated NFkB upregulates expression of the death receptor Fas and that knock-down of NFkB abrogates Pac-induced upregulation. Thus, our data supports a role for Dex antagonizing Pac through inhibition of Pac-induced NFkB transcription of Fas.

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