Roles of TTK Kinase in Breast Cancer Tumorigenesis Restricted; Files Only

King, Jamie (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/gh93gz54c?locale=en
Published

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

                       

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