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Articles 31 - 46 of 46

Full-Text Articles in Cancer Biology

The Role Of Mir-526b In Cox-2 Mediated Human Breast Cancer Progression And Induction Of Stem-Like Phenotype Via Ep4 Receptor Signaling, Erin O. Landman Jun 2014

The Role Of Mir-526b In Cox-2 Mediated Human Breast Cancer Progression And Induction Of Stem-Like Phenotype Via Ep4 Receptor Signaling, Erin O. Landman

Electronic Thesis and Dissertation Repository

Our laboratory previously established that aberrant expression of cyclo-oxygenase (COX)-2 promotes breast cancer progression and metastasis via multiple mechanisms, including stem-like cell (SLC) induction, owing to activation of the prostaglandin E2 receptor EP4. COX-2 expression was linked to up-regulation of miRNA-526b. We hypothesized that miR-526b is regulated by EP4 activity, and that miR-526b supports breast cancer progression and induction of SLCs. Using stably miR-526b transfected MCF-7 and SKBR-3 cells in functional assays, including tumorsphere formation in vitro and lung colony formation in vivo, we observed enhanced migration, invasion, proliferation, tumorsphere formation, and in vivo tumorigenecity compared to controls. EP4 ...


Sirna Targeting Of Thymidylate Synthase, Thymidine Kinase 1 And Thymidine Kinase 2 As An Anticancer Therapy: A Combinatorial Rnai Approach, Christine Di Cresce Apr 2014

Sirna Targeting Of Thymidylate Synthase, Thymidine Kinase 1 And Thymidine Kinase 2 As An Anticancer Therapy: A Combinatorial Rnai Approach, Christine Di Cresce

Electronic Thesis and Dissertation Repository

Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumour milieu, and may modulate resistance to TS-targeting drugs. We have previously shown that TS antisense molecules (oligodeoxynucleotides, ODNs, and small interfering siRNA, siRNA) sensitize tumour cells, both in vitro and in vivo, to TS targeting drugs. As both TS and TKs contribute to cellular ...


Distinct Roles Of Bmp And Lkb1/Ampk Signalling Impacting Ovarian Cancer Spheroid Biology, Teresa M. Peart Mar 2014

Distinct Roles Of Bmp And Lkb1/Ampk Signalling Impacting Ovarian Cancer Spheroid Biology, Teresa M. Peart

Electronic Thesis and Dissertation Repository

High-grade serous (HGS) carcinoma, the most prevalent and most deadly subtype of epithelial ovarian cancer (EOC), presents unique therapeutic challenges since the majority of cases are diagnosed at advanced, metastatic stage. At this point widespread intraperitoneal metastatic lesions are numerous, which is why models that recapitulate disease dissemination are critical to uncover novel therapeutic targets. One of the initiating events in ovarian cancer metastasis is shedding from the primary tumour into the peritoneal cavity where cells must survive in suspension in order to seed secondary tumours. This non-adherent population of cells exists as multicellular aggregates, or spheroids; data from our ...


The Effects Of Atypical Protein Kinase C On Tgfβ Signalling, Adrian D. Gunaratne Mar 2014

The Effects Of Atypical Protein Kinase C On Tgfβ Signalling, Adrian D. Gunaratne

Electronic Thesis and Dissertation Repository

The transforming growth factor beta (TGFβ) signalling pathway is an essential regulator of many cellular processes including epithelial growth control, epithelial to mesenchymal transition (EMT), apoptosis, and the establishment of developmental fate. Alterations in TGFβ signalling patterns are associated with various pathological disorders such as fibrosis and cancer. In recent years it has become clear that regulation of TGFβ signalling is dependent on the trafficking and endocytosis of the TGFβ receptors, however, the factors that control these processes are still under investigation.

In this thesis, I examined the role of Protein Kinase C (PKC) in the regulation of TGFβ signalling ...


Transforming Growth Factor-Beta Receptor Signalling Is Modulated By Integrin-Linked Kinase, Stellar H. Boo Nov 2013

Transforming Growth Factor-Beta Receptor Signalling Is Modulated By Integrin-Linked Kinase, Stellar H. Boo

Electronic Thesis and Dissertation Repository

Transforming growth factor-beta 1 (TGF-β1) modulates regeneration after injury through induction of fibroblast proliferation, migration, and differentiation into myofibroblasts. Induction of myofibroblast differentiation by TGF-β1 requires expression of integrin-linked kinase (ILK). I now show that ILK interacts with TGF-β receptor type II (TβRII) in primary dermal fibroblasts. Further, colocalization of ILK and TβRII can be observed at the cell membrane and in intracellular vesicles. The association of TβRII and ILK does not require TGF-β1 stimulation, kinase activity of TGF-β1 receptor type I or TβRII, and it does not involve interactions between ILK and focal adhesion-associated proteins. When this interaction is ...


Cx43 Reduces Melanoma Growth Within A Keratinocyte Microenvironment And During Tumorigenesis In Vivo, Mark J. Ableser Aug 2013

Cx43 Reduces Melanoma Growth Within A Keratinocyte Microenvironment And During Tumorigenesis In Vivo, Mark J. Ableser

Electronic Thesis and Dissertation Repository

Connexins have been frequently identified as tumor suppressors in many cancers, however, their role in melanoma tumorigenesis remains controversial. Here, we show that B16-BL6 mouse melanoma cells express low levels of Cx26 and Cx43, rendering them gap junctional intercellular communication (GJIC) deficient. Following ectopic expression of Cx26 and Cx43, gap junction-like plaques were evident at the cell surface and the incidence of dye transfer was significantly increased similar to connexin-rich keratinocytes. The expression of Cx43, but not Cx26, significantly reduced proliferation and anchorage-independent growth relative to controls, whereas migration was unaffected. Additionally, Cx43-expressing melanoma cells displayed significantly reduced growth amongst ...


Characterizing The Role Of The Retinoblastoma Protein Lxcxe Binding Cleft In Cellular Senescence And Tumor Suppression, Srikanth Talluri Jul 2013

Characterizing The Role Of The Retinoblastoma Protein Lxcxe Binding Cleft In Cellular Senescence And Tumor Suppression, Srikanth Talluri

Electronic Thesis and Dissertation Repository

The Retinoblastoma protein (pRB) is a key regulator of the cell cycle and is functionally inactivated in most cancers. pRB has been proposed to utilize simultaneous interactions with E2F transcription factors and chromatin regulatory proteins to repress transcription and block cell cycle progression. The goal of this study is to characterize the physiological role of pRB interactions with chromatin regulatory proteins. I used gene targeted mice carrying point mutations in the murine Rb1 gene (Rb1∆L) that specifically disrupt pRB’s LXCXE binding cleft, and thereby its ability to interact with chromatin regulatory proteins while leaving its ability to bind ...


Features Of Dormancy In Metastatic Ovarian Cancer Cells, Rohann Jm Correa Jul 2013

Features Of Dormancy In Metastatic Ovarian Cancer Cells, Rohann Jm Correa

Electronic Thesis and Dissertation Repository

The most prevalent subtype of ovarian cancer – high-grade serous (HGS) carcinoma – is also the most lethal, since the majority of cases are characterized by advanced-stage (metastatic) presentation. Metastasis of this cancer proceeds by an intra-peritoneal route, involving detachment of cells from the primary tumour and dissemination throughout the peritoneal cavity as multicellular aggregates, or spheroids. Herein, we demonstrate that HGS patient-derived tumour cells cultured to form in vitro spheroids exhibit features of cancer dormancy, a cellular state known to promote therapeutic resistance and disease recurrence. We discovered that upon spheroid formation, cells became non-proliferative, exhibiting a cell cycle profile and ...


Systematic Analysis Of Residues In Conserved Region 3 Of The Human Papillomavirus 16 E7 Oncoprotein, Biljana Todorovic May 2013

Systematic Analysis Of Residues In Conserved Region 3 Of The Human Papillomavirus 16 E7 Oncoprotein, Biljana Todorovic

Electronic Thesis and Dissertation Repository

Although remarkable biological diversity is exhibited by viruses, as obligate intracellular parasites, they rely on host cell functions. As such, viruses typically must overcome a set of host barriers that prevent infection. For human papillomaviruses (HPV) one of these barriers is the state of terminal differentiation of the host cell. For that purpose HPVs encode two major oncoproteins, E6 and E7, which combine their efforts to effectively uncouple cellular differentiation from the cell cycle arrest. The E7 proteins have no intrinsic enzymatic activity or DNA binding ability, but they bind and manipulate numerous host proteins. E7 is a modular oncoprotein ...


Investigating The Interplay Between Protein Kinases And Caspases, Jacob P. Turowec Mar 2013

Investigating The Interplay Between Protein Kinases And Caspases, Jacob P. Turowec

Electronic Thesis and Dissertation Repository

The balance between cell survival and death is a crucial process in human development and tissue homeostasis, but is also misregulated in disease. In large part, apoptosis is controlled by caspases, a hierarchical series of cysteine aspartic acid proteases that demolish the cell by cleaving key structural and enzymatic proteins, but emerging paradigms have highlighted the ability of kinases to regulate caspase activity. One way in which kinases can control the progression of apoptosis is through phosphorylation of caspase substrates, which acts to prevent caspase cleavage of that target.

In this thesis, we develop new strategies to study this regulatory ...


Functional Significance Of Ilk-Elmo2 Interactions In Epidermal Keratinocytes, Ernest Ho Dec 2012

Functional Significance Of Ilk-Elmo2 Interactions In Epidermal Keratinocytes, Ernest Ho

Electronic Thesis and Dissertation Repository

The epidermis consists of a basal layer of undifferentiated keratinocytes and multiple suprabasal layers of differentiated keratinocytes. Undifferentiated keratinocytes are adherent and highly motile, whereas differentiated keratinocytes are comparatively less motile and downregulate cell attachments to the extracellular matrix. Integrin-linked kinase (ILK) is a scaffold protein implicated in the regulation of many cellular functions in keratinocytes, including cell attachment, migration, phagocytosis, and protein trafficking. To determine the mechanisms by which ILK is involved in these processes, I sought to identify other proteins which may interact with ILK in keratinocytes. I identified Engulfment and Cell Motility 2 (ELMO2) to interact with ...


Timp-2 Decreases The Invasive Potential Of Mcf-7 And Mdamb-231 Cells Independent Of Mmp Inhibition, Mario Cepeda Dec 2012

Timp-2 Decreases The Invasive Potential Of Mcf-7 And Mdamb-231 Cells Independent Of Mmp Inhibition, Mario Cepeda

Electronic Thesis and Dissertation Repository

Tissue Inhibitors of Metalloproteinases (TIMPs) are the natural inhibitors of Matrix Metalloproteinases (MMPs), a family of proteins primarily responsible for Extracellular Matrix (ECM) remodeling. TIMP-2 is a special member of the TIMP family as it is both an inhibitor and promoter of MMP activity, and can also bind the cell surface and signal inside the cell to influence cell behavior. In this study, MDAMB-231 and MCF-7 breast cancer cells were treated with physiological concentration of TIMP-2, which decreased the invasive potential of both cell lines. This was independent of MMP inhibition, and instead a decrease in the expression and secretion ...


Characterization Of A Tumour Suppressor Function Of Ranbpm, Elnaz Atabakhsh Nov 2012

Characterization Of A Tumour Suppressor Function Of Ranbpm, Elnaz Atabakhsh

Electronic Thesis and Dissertation Repository

Ran-binding protein M (RanBPM) is an evolutionarily conserved nucleocytosolic protein that has been proposed to regulate various cellular processes, including protein stability, gene expression, receptor-mediated signalling pathways, cell adhesion, development, and apoptosis. Despite the multitude of functions attributed to RanBPM however, little is known regarding the precise mechanisms by which RanBPM executes these cellular roles. In this work, we seek to address this matter by describing functions for RanBPM in the regulation of apoptotic and pro-survival signalling pathways, and in cellular transformation.

We first identify RanBPM as a pro-apoptotic protein that regulates the activation of the intrinsic apoptotic signalling pathway ...


The Embryonic Protein Nodal Supports Metastatic Phenotypes In Breast Cancer, Daniela F. Quail Jun 2012

The Embryonic Protein Nodal Supports Metastatic Phenotypes In Breast Cancer, Daniela F. Quail

Electronic Thesis and Dissertation Repository

Metastasis is the process by which tumour cells disseminate to distant organ sites. Aberrant expression of stem cell-associated proteins within tumours is associated with metastasis and poor patient prognosis. One example of a stem cell factor that is associated with cancer progression is Nodal, a member of the TGF-β superfamily. Nodal is normally limited to pluripotent stem cells during embryonic development, and to specialized dynamic adult tissue (such as the cycling endometrium), but is aberrantly re-expressed in multiple cancer types, including melanoma, glioma, prostate cancer, and pancreatic cancer. The central objective of this thesis is to determine the role of ...


Metastatic Disease: Interactions Between Tumor Cells And Host Environment During Cancer Cell Spread, Jennifer M. Maclean Jul 2011

Metastatic Disease: Interactions Between Tumor Cells And Host Environment During Cancer Cell Spread, Jennifer M. Maclean

Electronic Thesis and Dissertation Repository

Tumor and metastasis formation are not cell autonomous phenomena, but rather an evolution of disease within and responding to the host environment. Metastatic spread from a primary tumor occurs as a result of a complex interplay between tumor cells and the host, wherein tumor cells must escape the primary tumor, enter the host vasculature, travel to and arrest in a distant tissue and survive and grow in that new organ. It is known that cells that progress through these stages must both escape and exploit host systems, yet the mechanisms used are not fully understood. Therefore, the goal of this ...


Regulation Of Dna Damage Processing By Covalent Modification Of Thymine Dna Glycosylase, Ryan D. Mohan May 2010

Regulation Of Dna Damage Processing By Covalent Modification Of Thymine Dna Glycosylase, Ryan D. Mohan

Electronic Thesis and Dissertation Repository

Thymine DNA glycosylase (TDG) is an essential DNA repair enzyme mediating excision of uracil and thymine mispaired with guanine within CpG contexts. Unrepaired, these lesions result in G:C to A:T transitions which are major contributors to genome instability. Interestingly, TDG interacts functionally with transcriptional regulators and participates in directed cytosine demethylation at promoters. TDG is subject to multiple post-translational modifications (PTM) and we undertook an analysis of how these regulate TDG function. Initially, we examined TDG regulation by small ubiquitin-like modifier (SUMO) and identified a novel SUMO binding motif (SBM1, residues 144-148). We hypothesized that SBM1, along with ...