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published_or_final_version / abstract / Biological Sciences / Master / Master of Philosophy

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<p>The ABL family of non-receptor tyrosine kinases, ABL1 (also known as c-ABL) and ABL2 (also known as Arg), links diverse extracellular stimuli to signaling pathways that control cell growth, survival, adhesion, migration and invasion. ABL tyrosine kinases play an oncogenic role in human leukemias. However, the role of ABL kinases in solid tumors including breast cancer progression and metastasis is just emerging. </p><p>To evaluate whether ABL family kinases are involved in breast cancer development and metastasis, we first analyzed genomic data from large-scale screen of breast cancer patients. We found that ABL kinases are up-regulated in invasive breast cancer patients and high expression of ABL kinases correlates with poor prognosis and early metastasis. Using xenograft mouse models combined with genetic and pharmacological approaches, we demonstrated that ABL kinases are required for regulating breast cancer progression and metastasis to the bone. Using next generation sequencing and bioinformatics analysis, we uncovered a critical role for ABL kinases in promoting multiple oncogenic pathways including TAZ and STAT5 signaling networks and the epithelial to mesenchymal transition (EMT). These findings revealed a role for ABL kinases in regulating breast cancer tumorigenesis and bone metastasis and provide a rationale for targeting breast tumors with ABL-specific inhibitors.</p> / Dissertation

Matrix Metallopeptidase 1 (MMP-1) expression has repeatedly been correlated to tumorigenesis and metastasis. Yet, MMP-1 regulation in a metastatic context remains largely unknown. Here we confirm differential MMP-1 expression in mammary carcinoma cells with varied metastatic potentials and identify a mechanism differentially regulating MMP-1. We show that MMP-1 expression is regulated by an AP-1 element in its promoter in highly metastatic MDA-MB-231 mammary carcinoma cell derivatives. Fra-1, an AP-1 family transcription factor, differentially binds this element in highly metastatic derivatives compared to low-metastatic cells and is required for MMP1 expression. Fra-1 mRNA levels are unchanged in the cell variants, however its protein levels are higher in the metastatic cells. There was no change in protein degradation rates, while protein synthesis rates of Fra-1 increased. These results suggest that protein translation of Fra-1 is differentially regulated in these cells. Consistent with the importance of Fra-1 for tumor growth, we found that Fra-1 overexpression is sufficient to increase cell motility and anchorage independent growth. These results suggest that Fra-1 regulation is critical for regulation of MMP-1 and metastasis.

The vertebral column is the most common site of skeletal metastatic development secondary to breast cancer. Multiple clinical treatments are available for spinal metastasis, including systemic bisphosphonates and radiation therapy, however the success of current treatment approaches varies considerably. Alternative treatment strategies for spinal metastatic destruction must be aimed at both reducing tumor burden and restoring mechanical stability. Photodynamic therapy (PDT) has been shown to be successful at destroying osteolytic lesions in preclinical models of breast cancer spinal metastasis. However, the clinical feasibility of PDT for spinal metastasis is dependent on its potential effects on the structural integrity of vertebral bone. This thesis aims to determine the effects of PDT alone and in combination with bisphosphonate therapy on the structural architecture and mechanical properties of healthy and metastatically involved vertebrae. PDT was shown to have a positive effect on vertebral bone structure, alone and in combination with previous bisphosphonate therapy.