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Breast cancer remains the most common malignant disease in women worldwide. Despite the advantages of early detection and improved treatments, studies into the mechanisms that initiate and drive breast cancer progression are still required. Recent studies have identified RUNX1, which is an essential transcription factor for hematopoiesis, is one of the most frequently mutated genes in breast cancer patients. However, the role of RUNX1 in the mammary gland is understudied. In this dissertation, we examined the role of RUNX1 in both normal mammary epithelial and breast cancer cells. Our in vitro studies demonstrated that RUNX1 inhibits epithelial to mesenchymal transition (EMT), migration, and invasion, reflecting its tumor suppressor activity, which was confirmed in vivo. Moreover, RUNX1 also contributes significantly to inhibition of the phenotypes of breast cancer stem cells (CSC), which is responsible for metastasis and tumor relapse. We showed that Runx1 overexpression reduces the tumorsphere formation and cancer stem cell population. Overall, our studies provide mechanistic evidence for RUNX1 repression of EMT in mammary cells, anti-tumor activity in vivo and regulation of CSC-like properties in breast cancer. Our results highlight crucial roles for RUNX1 in preventing epithelial to mesenchymal transition and tumor progression in breast cancer. This RUNX1 mediated mechanism points to novel intervention strategies for early stage breast cancer.

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This thesis is divided into three chapters. In each case, the goal is to achieve inhibition of a growth kinase (PIM or AXL) and subsequent arrest of cell growth and induction of apoptosis (in vitro cell culture models) or decrease in tumor volume (in vivo xenograft studies). Chapter one and chapter two discuss inhibition of proviral integration site for Moloneymurine leukemia virus (PIM) kinases. The three PIM kinases, PIM-1, PIM-2, and PIM-3, are a subfamily of serine/threonine kinases that are known to be involved in signaling pathways as downstream effectors of signal transducer and activator of transcription-5 (STAT5) signaling and inhibitors of apoptosis. PIM kinases are implicated in a large percentage of hematological malignancies and solid tumors. Because they have been shown to correlate with disease progression and poor prognosis in many of these conditions, PIM kinase inhibitors are being developed and investigated for therapeutic use. The aim of this study in chapter one was to evaluate the role of PIM 1, 2 and 3 in urothelial carcinomas, using second generation Pan-PIM kinase inhibitor TP-3654. Retrospective immunohistochemical analysis of bladder cancer specimens found that PIM 1, 2, and 3 was expressed in a significant number of cases. PIM-1 was expressed in 4 bladder cancer cell lines and TP-3654 treatment was able to inhibit BAD phosphorylation to induce apoptosis. The second aim of this study was to investigate the effects of TP-3654 on the interaction of c-MYC with PIM kinase family members. The data indicate that PIM-1 only interacts with c-MYC in the acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines studied, and that PIM-1 siRNA knockdown or treatment with TP-3654 is able to decrease this interaction. The third chapter discusses inhibition of the receptor tyrosine kinase Axl. Pancreatic cancer is a highly lethal disease characterized by malignant cells that rapidly disseminate from the primary tumor to form local and distant metastases. Axl is overexpressed in over 50% of pancreatic cancers and expression of Axl in these cancers is highly associated with a poor prognostic outcome for patients. Small molecule inhibitors of AXL are currently under investigation, as AXL is associated with cell migration mediated by epithelial-mesenchymal transition (EMT). The aim of this study was to investigate the effects of a small molecule inhibitor of AXL, TP-0903, on pancreatic cancer cell lines. Consistent with the known function of Axl, TP-0903 inhibited Gas6-induced migration and invasion of pancreatic cancer cells invitro and potently induced apoptosis. Additionally, we found that inhibition of AXL decreased expression of EMT marker genes and induced mesenchymal pancreatic cancer cell lines to take on an epithelial phenotype. TP-0903 also significantly inhibited the growth of pancreatic cancer cell lines grown in xenograft tumor mouse model and taken together, the results suggest Axl is a potential therapeutic target in pancreatic cancer and TP-0903 as a potential therapeutic agent.

The traditional picture of tissues, where they are treated as liquids defined by properties such as surface tension or viscosity has been redefined during the last few decades by the more fundamental question: under which conditions do tissues display liquid-like or solid-like behaviour? As a result, basic concepts arising from the treatment of tissues as solid matter, such as cellular jamming and glassy tissues, have shifted into the current focus of biophysical research. Here, we review recent works examining the phase states of tissue with an emphasis on jamming transitions in cancer. When metastasis occurs, cells gain the ability to leave the primary tumour and infiltrate other parts of the body. Recent studies have shown that a linkage between an unjamming transition and tumour progression indeed exists, which could be of importance when designing surgery and treatment approaches for cancer patients

The inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen-deprivation therapy (ADT) and accumulated resistance mechanisms to evade androgen receptor (AR) suppression. Whereas the canonical androgen/AR signaling axis maintains prostate cell growth, differentiation and survival, in prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogenous, ADT-resistant tumor that culminates in prostate tumor cells transitioning from epithelial to mesenchymal states (EMT) and the development of metastatic castration-resistant prostate cancer (mCRPC). Here, we examined prostate cancer cell lines that model common CRPC subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and ExtraTerminal (BET – BRD2, BRD3 and BRD4) family of proteins, to test the hypothesis that each BET family member regulates EMT and underlying characteristics such as cell motility and invasiveness. We systematically manipulated the BET proteins and found that BRD4 regulates cell migration and invasion across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate cell migration and invasion in less aggressive models that retain AR expression or signaling. We determined that BRD4’s contribution to this process occurs through the transcriptional regulation of AHNAK, SNAI1 and SNAI2, which are EMT genes linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits EMT and metastatic potential. Overall, these results reveal a novel, BRD4-regulated EMT gene signature that may be targetable to treat metastatic castration-resistant prostate cancer.

Perivascular adipose (PVAT) has been hypothesized to influence arterial health, where an excess can lead to pathogenesis of atherosclerosis and other arterial pathologies. A novel assessment of carotid PVAT is the use of carotid extra media thickness (EMT) ultrasonography. Currently, there is a lack of research to demonstrate the relationship between carotid EMT and existing measures of arterial health, notably, central pulse wave velocity, and carotid distensibility and intimal media thickness. In the current cross sectional study, 81 participants of younger recreationally active (ages 23.2 ± 2.5 years), younger sedentary (ages 26.4 ± 7.2 years), older healthy (ages 70.3 ± 5.4 years) and older adults with coronary artery disease (CAD) (ages 67.9 ± 8.7 years) were recruited. Resting measures of central arterial stiffness was examined through the assessment of aPWV, while measures of local carotid stiffness were examined through carotid distensibility. Aortic PWV was calculated using an accepted direct distance method (80% of carotid to femoral direct distance) and time difference between the feet of the carotid and femoral waveforms. Carotid intima-media thickness (IMT), a measure of the inner arterial walls, and carotid extra media thickness (EMT), a measure of carotid PVAT, were assessed through B-mode ultrasound images and a semi-automated edge tracking software. Carotid EMT, IMT, and aPWV were significantly greater in older adults than in younger adults (p < 0.05). No difference in carotid EMT was found between younger recreationally active (0.47 ± .08 mm) and sedentary adults (0.46 ± .06 mm). There were also no differences in carotid EMT between the older healthy (0.58 ± .06 mm) and older adults with CAD (0.54 ± 0.08 mm). Carotid EMT was also significantly correlated with age (r =0 .500), waist circumference (r = 0.521), aPWV (r =0.431), carotid distensibility (r = -0.364 and IMT (r = 0.404). Despite significant correlations, carotid EMT was not an independent predictor of aPWV, carotid distensibility and IMT. Because of the lack of predictive power in measures of arterial stiffness and carotid IMT, there is a potential that carotid EMT may be an independent vascular disease marker. Future investigations should involve carotid EMT in longitudinal studies to evaluate the potential marker for a more comprehensive cardiovascular risk assessment. / Thesis / Master of Science (MSc)

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