Roles of TTK Kinase in Breast Cancer Tumorigenesis Público
King, Jamie (Spring 2018)
Abstract
Cancer formation is enabled by genetic changes that control cell division, which alters how genetic information is transferred and contributes to malignant cell transformation. TTK is a mitotic kinase that is overexpressed in several cancer types, including breast cancer. While the roles of TTK in centrosome duplication and the spindle assembly checkpoint have been well characterized, the complete functional roles of TTK in cancer have not been studied. The research in this dissertation describes diverse roles of TTK in breast cancer tumorigenesis.
One well characterized role of TTK is in the control of the centrosome duplication cycle and formation of the mitotic spindle. Previous studies have shown centrosome amplification (greater than 2 centrosomes) to be associated with genomic instability and worse patient outcomes in breast cancer. We found a positive correlation between TTK expression and centrosome amplification (CA) in breast cancer cells, as well as a correlation between TTK overexpression and worse prognosis in breast cancer patients. We also determined that targeting TTK could attenuate proliferation and CA in cell lines that have high frequencies of CA.
More recently, mitotic kinases like Aurora A and PLK4 have been shown to have roles in supporting cell phenotypes that promote cancer cell invasion and metastasis. In addition to establishing a role of TTK in promoting CA, we also found that targeting TTK can attenuate the mesenchymal phenotype of aggressive triple negative breast cancer cells through various mechanisms, including TGF-β signaling, KLF5 and micro-RNAs.
In further studies, we hypothesized that TTK could also mediate radiosensitivity in breast cancer, since it has been reported that substrates in the DNA repair signaling pathway and targeting some downstream TTK substrates has shown effectiveness in radiosensitization. From this line of investigation, we also found that targeting TTK could sensitize radioresistant breast cancer cells by enhancing apoptotic signaling and minimizing active DNA repair.
Overall, this work highlights the diverse cellular processes through which TTK overexpression promotes breast cancer tumorigenesis. This provides rationale to further develop targeted inhibitors against TTK in breast cancer and other types of cancer.
Table of Contents
Table of Contents
Chapter 1: Introduction Pages 1-27
1.1 Cancer
1.1.1 Cancer overview 2
1.1.2 Cancer hallmarks 2-3
1.1.3 Breast cancer 3-5
1.2 Chromosome instability, aneuploidy and mitosis in cancer
1.2.1 Overview 6-7
1.2.2 Critical factors of centrosome amplification (CA) 7-9
1.2.3 Role of CA in cancer 9-11
1.3 Invasion and metastasis
1.3.1 Overview 11-12
1.3.2 Epithelial to mesenchymal transition 12
1.3.3 EMT signaling 12-13
1.3.4 KLF5 in EMT 13-15
1.4 Links between altered mitosis and EMT 15-16
1.5 Prognosis and treatment responses in patients 16
harboring changes in CA and mitotic genes
1.6 TTK Kinase
1.6.1 Background 17
1.6.2 Normal functions and structure 18-19
1.6.3 Non-canonical roles 19
1.6.4 TTK in cancer 20-21
1.7 Rationale for studying TTK in breast cancer 21-22
and goals of dissertation
Figures 23-27
Chapter 2: Differential expression of TTK Pages 28-44
in breast cancer cells supports CA
2.1 Introduction 29-30
2.2 Materials and Methods 30-33
2.3 Results 34-37
2.4 Discussion 37-38
Figures 39-44
Chapter 3: TTK promotes mesenchymal signaling Pages 45-78
via multiple mechanisms in triple negative breast cancer
3.1 Abstract 46
3.2 Introduction 47-49
3.3. Materials and Methods 49-54
3.4 Results 54-63
3.5 Discussion 63-67
Figures 68-78
Chapter 4: Effects of targeting TTK in Pages 79-97
radioresistant breast cancer cells
4.1 Introduction 80-82
4.2 Materials and Methods 82-85
4.3 Results 85-90
4.4 Discussion 88-90
Figures 91-97
Chapter 5: Discussion Pages 98-108
5.1 Summary and conclusions 99
5.2 Novel role of TTK in promoting CA in breast cancer 99-100
5.3 Novel role of TTK in mediating EMT in aggressive 100-101
breast cancer
5.4 Exploration of TTK as a mediator of radiosensitivity 101-102
5.5 Proposed mechanisms for how TTK overexpression facilitates 102-103
CA, EMT and radioresistance
5.6 Future directions 103-106
5.7 Contributions to the field and larger implications 106
for clinical investigations of TTK
Figures 107-108
References Pages 109-122
About this Dissertation
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