Date of Award

Winter 2017

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Jochen H.M. Prehn

Funder/Sponsor

Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT

Keywords

Breast Neoplasms, Drug Therapy

Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer, which accounts for 15-20% of this disease and is currently treated with genotoxic chemotherapy. The BCL2 (B-cell lymphoma 2) family of proteins controls the process of Mitochondrial Outer Membrane Permeabilization (MOMP), which is required for the activation of the mitochondrial apoptosis pathway in response to genotoxic agents. We previously developed a deterministic systems model of BCL2 protein interactions, DR_MOMP that calculates the sensitivity of cells to undergo mitochondrial apoptosis. Here, we determined whether DR_MOMP predicts responses of TNBC cells to genotoxic agents and the re-sensitization of resistant cells by BCL2 inhibitors. Using absolute protein levels of BAX, BAK, BCL2, BCL(X)L and MCL1 as input for DR_MOMP, we found a strong correlation between model predictions and responses of a panel of TNBC cells to cisplatin (R2 = 0.96) and paclitaxel treatments (R2 = 0.94). This outperformed single protein correlations (best performer BCL(X)L) and BCL2 proteins ratio). Recently, several reports highlighted the function of BCL2 proteins in the regulation of other cellular aspects, such as metabolism. In this work, we used a single cell time-lapse microscopy approach to analyse the contribution of BCL2 and BCL(X)L in the regulation of breast cancer bioenergetics. We studied the ATP and the mitochondrial membrane potential kinetics of breast cancer cells under different conditions. We found that overexpression of BCL2 and BCL(X)L led to a metabolic advantage of ER+ breast cancer cells, which is potentially linked to increased tumour progression.

Additionally, we observed that the treatment with BCL2 selective inhibitors, which have now entered clinical trials, alters mitochondrial metabolism and dynamics. We further demonstrate that combination treatment of BCL2 antagonists with a glycolytic inhibitor, 2-deoxy-D-glucose, is a potential treatment for ER+ and TN breast cancer.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

12 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2017.

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