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Assessing The Outcomes Of Blocking Ccl2-Ccr2 Signaling Axis On Breast Cancer Brain Metastasis, Yutao Qi

Dissertations & Theses (Open Access)

Breast cancer brain metastases have remained one of the most intense challenges for precision cancer therapeutics, but current treatment options are limited and not curative. Recently, our lab reported that adoptive PTEN downregulation in metastatic breast tumor cells activates PI3K/NF-ƙB signaling and increases the secretion of the chemokine CCL2, which enhances the chemotaxis of CCR2⁺ myeloid cells, a major subpopulation of bone marrow-derived myeloid cells (BMDMs), from peripheral blood into the brain tumor microenvironment (TME), eventually promoting brain metastasis outgrowth by driving immune suppression. Here, in this project we have been aiming to develop effective therapies by immune-modulating the …

Defying The Darkness: Countering Cancer With Light, Travis Hankins

Honors Theses

Triple-Negative Breast Cancer (TNBC) accounts for upwards of 15% of reported breast cancer cases. This subtype of breast cancer poses a greater threat to those diagnosed as compared to other types of breast cancer due to the lack of treatment options available. Additionally, TNBC grows and spreads faster, tends to be more aggressive, and has a greater chance of recurrence than its counterparts. Altogether, TNBC cases generally have a worse prognosis over other types of breast cancer. Photodynamic therapy (PDT) is currently being researched as a way to treat TNBC. Photodynamic therapy agents are light-activated materials used for localized disease …

The Age-Dependent Characterization Of The Er-Alpha Positive Breast Cancer Tumor Microenvironment, Katie Marie Hamel

LSU Doctoral Dissertations

In disease states such as cancer, endocrine and paracrine signals from adipose tissue contribute to cancer progression and drug resistance. Young individuals diagnosed with estrogen receptor-alpha positive (ER-a+) breast cancer have an observed increase in resistance to endocrine therapies. This suggests that an alternative estrogen signaling pathway is active within these tumors. Despite this, the effects of stromal age on the endocrine response in breast cancer is not well known. Here, we review and highlight the involvement of the stromal age in both tumorigenesis and physiological wound healing. To identify specific differences between young and aged ER-a+ breast tumors, RNA …

Characterization Of Alcohol-Mediated Promotion Of Breast Cancer Stem Cells, Mckenna Below

Master's Theses

Breast cancer is the leading cause of cancer-related death in women globally, and one in eight women will be diagnosed with breast cancer at some point in her life. Alcohol consumption has been linked to increase breast cancer risk and increased risk of tumor recurrence. Understanding the molecular mechanisms of modifiable lifestyle factors such as alcohol consumption will help to lower these risks and design more effective therapeutic approaches. Estrogen Receptor positive (ER+) breast cancer comprises approximately 70% of all breast cancers, and these tumors are effectively targeted by endocrine therapy in the form of estrogen deprivation with aromatase inhibitors, …

Association Between Plasma Genistein And Health-Related Quality Of Life In Breast Cancer Survivors, Tran Pham

Honors Undergraduate Theses

According to the American Cancer Society, breast cancer is the most commonly diagnosed cancer and is the second leading cause of cancer death in American women. Breast cancer screenings and improvement in treatments have resulted in the rising number of survivors in the recent decade. This urged the need for post-diagnosis lifestyle changes to improve breast cancer patients' quality of life. Many studies found soy food, the primary dietary source of phytoestrogens, has a protective effect against breast cancer recurrence and mortality. Dietary phytoestrogens can be classified into two groups: isoflavones and lignans. Daidzein and genistein were identified as the …

Awareness Of Genetic Predispositions That Increase The Risk Of Breast Cancer, Carly Huber

Honors Undergraduate Theses

Breast cancer is the most commonly diagnosed cancer in women in the United States and is the leading cause of cancer-related death among women worldwide. Certain demographics, such as racial/ethnic, age, and gender groups, are underrepresented in breast cancer studies. This lack of representation results in issues with creating genetic tests, as variants associated with those groups are not being detected. Furthermore, these underrepresented demographics are receiving a worse prognosis than those that are overrepresented in research. This study aimed to understand how informed the understudied racial/ethnic, gender, and age populations are regarding breast cancer and genetic testing compared to …

Prolactin Drives A Dynamic Stat5a/Hdac6/Hmgn2 Cis-Regulatory Landscape Exploitable In Er+ Breast Cancer, Justin M. Craig

Theses and Dissertations

The hormone prolactin has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome-wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin induced, STAT5A mediated gene expression. Here, multi-condition STAT5A, HDAC6, and HMGN2 ChIP-seq with parallel condition RNA-seq are utilized to reveal the cis-regulatory landscape and cofactor dynamics underlying prolactin stimulated gene expression in breast cancer. We find that prolactin regulated genes are …

Mimicking The Effect Of Prolactin On Stat3/Stat5 Activity In Breast Cancer, Jennifer N. Barbuto, Sarah R. Walker

Honors Theses and Capstones

Signal transducers and activators of transcription (STAT) 3 and 5 are commonly constitutively activated in breast cancer. STAT5 can outcompete STAT3 and reduce cell proliferation and metastasis. STAT5 activation is stimulated by prolactin, a natural hormone that can be harmful at high levels. The aim of this study is to identify some possible previously developed drugs that mimic the effect of prolactin and STAT5 without the added risk in MDA-MB231 breast cancer cells. Using the CLUE database query app and STAT5 up- and downregulation signatures, three drugs (X, K, and M) were chosen based on their similarity in signatures to …

Nuclear Aurora-A Kinase-Induced Hypoxia Signaling Drives Dissemination And Metastasis In Breast Cancer., Kristina Marinak Whately

Graduate Theses, Dissertations, and Problem Reports

Metastatic breast cancer causes the vast majority of cancer-associated deaths, especially in triple negative breast cancers (TNBC). TNBC is still poorly understood and has no effective treatment. Here we reveal that presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia induced factor-1) signaling. The nuclear AURKA in the complex with constitutively expressed HIF-1β subunit activates transcription of “hypoxia induced genes” under normoxic conditions (the phenomenon called pseudohypoxia) without upregulation of oxygen-sensitive HIF-1α subunit. We uncover that AURKA preferentially binds to and phosphorylates HIF-1β, and co-localizes with HIF complex on DNA. The mass …

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Prevalence Of Brca1 And Brca2 Mutations Among Breast And Ovarian Cancer Patients In Northern Emirates, Zahra Ahmed Mohammed Saeed

Theses

Breast Cancer (BC) is the most common cancer and the second most cause of death among women. Mutations in BRCA1 and BRCA2 genes confer high susceptibility to both breast and ovarian cancer. However, data on the prevalence of the BRCA1/2 mutations among breast and ovarian cancer patients is limited. The genetic component of breast cancer in the UAE is largely unknown and no study has evaluated the BRCA mutations status in breast and ovarian cancer patients in the UAE population. This retrospective study aimed to establish mutation frequencies of the BRCA genes in breast and ovarian cancer patients from the …

Pvt1 Exon 9 A Regulator Of Claudin Expression In Triple Negative Breast Cancer, Fayola Levine

Theses and Dissertations

Claudin low triple negative breast cancer (TNBC) has the worst clinical outcomes in comparison to other breast cancer subtypes. The underlying molecular mechanisms associated with the aberrant expression of claudins are not well understood. The transcript from PVT1 exon 9 is a regulator of claudin expression, and migration, in TNBC.

Breast Cancer Sub-Clones That Metastasize To Lung And Bone Exhibit Different Metabolic Preferences, Mollie Merrell

Honors Theses

Metastasis is responsible for the majority of cancer related deaths. In breast cancer the lungs and bones are the major sites for metastasis. Previous studies used the metastatic aggressive MDA-MB-231 breast cancer line to isolate sub-clones that preferentially invade the lungs (LM line) or bones (BoM line). While genes associated with the tissue specific metastasis have been identified, it is unknown if metabolic adaptations contribute to the growth of the LM and BoM lines in their respective organs. The goal of this study was to test the hypothesis that the LM and BoM lines exhibit differences in glucose and glutamine …

Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz

Honors Theses

Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor …

Cell Proliferation And Viability Inhibition By Resveratrol On Breast Cancer Cell Lines, Kyle Ford Gordon Jr

Honors Theses

Antioxidants are well-known for their various health benefits. They are able to protect cells from being damaged by free radicals that are produced by vital biochemical processes. It has long been known that antioxidants are important in our everyday health, but their potential as disease preventers and potential therapeutic agents is a relatively new field of study. Resveratrol, a natural polyphenol and well-known antioxidant, is found in plants, fruits, and products derived from them, like red wine. Resveratrol has been shown to have various properties, including antiaging, anti-aggregation of platelets, anti-inflammatory, and anticancer activities. Because of their many health benefits, …

The Effects Of Largazole, A Histone Deacetylase Inhibitor, On Breast Cancer Cell Viability And Metastasis, Hannah Mccowan

Honors Theses

Histone deacetylase enzymes modify epigenetic characteristics of a genome by removing acetyl groups from histone proteins in chromatin. Histone deacetylase inhibitors work by stopping this activity which can have various results in a cell including apoptosis, cell cycle arrest, differentiation, and migration. The purpose of these experiments was to see how largazole, a histone deacetylase inhibitor, affected cell viability for breast cancer and associated metastatic cell lines in both normoxic and hypoxic conditions. The experiment was completed by setting up two 96-well plates with varying concentrations of largazole and conducting a sulforhodamine viability assay. The specific cell lines used in …

Phytochemical Content And Anti-Breast Cancer Activity Of Kentucky Native Plants., Nicole A. Mcgrath

College of Arts & Sciences Senior Honors Theses

Plants are a proven and rich source of chemical diversity for the development of pharmaceuticals. Plants that are native to Kentucky are an underexplored resource that could lead to advances in treating human diseases such as cancer. Kentucky native plants, especially those with highly diverse or enriched chemical compositions are possible leads for therapeutic drug development. To explore the potential of native Kentucky plants for treatment of breast cancer, a list of prospective target plants was developed based on literature reports. This list was narrowed to 10 tissues for further in-depth chemical analysis including estimation of alkaloids, terpenes, and phenolics, …

The Role Of Apkcs And Apkc Inhibitors In Cell Proliferation And Invasion In Breast And Ovarian Cancer, Tracess B. Smalley

USF Tampa Graduate Theses and Dissertations

Research has demonstrated that the atypical protein kinase C-zeta (PKC-ζ) is a component of many dysregulated pathways in breast and ovarian cancer, including cellular proliferation, survival, and cell cycle upregulation. Breast and ovarian cancers affect women every day and are second and fifth leading cause of cancer death. Women who seek treatments are commonly met with invasive surgeries or chemotherapy. Protein kinase C (PKC) is a family of serine and threonine phosphorylating kinases that have been shown to modulate and transduce signaling cascades that play roles in the development and survival of cancers. Atypical PKC (aPKC), have been heavily suggested …

Breast Cancer Associated Muscle Fatigue: Novel Targets To Improve Survival And Quality Of Life, Hannah Elizabeth Wilson

Graduate Theses, Dissertations, and Problem Reports

Women diagnosed with breast cancer (BC) currently represent the largest group of cancer survivors in the United States, accounting for over 20% of those living after a cancer diagnosis. Most BC survivors report an unusual degree of fatigue, which can present prior to diagnosis and continue for many years after treatment cessation. Recent studies show that deficits in muscle function predict shorter survival in cancer, perhaps due to the fact that fatigue is known to reduce a patient’s tolerance to anti-cancer therapies. Therefore, improving muscle function in BC patients has the potential to improve both quality of life and survival …

The Human Intermediate Prolactin Receptor: A Breast Cancer Proto-Oncogene, Jacqueline M. Grible

Theses and Dissertations

The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. hPRLrI co-expression with full-length hPRLr (hPRLrL) in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce …

Markov Decision Process Approach To Strategize National Breast Cancer Screening Policy In Data-Limited Settings, Vijeta Deshpande

Masters Theses

Early diagnosis is a promising strategy to reduce premature mortalities and for optimal use of resources. But the absence of mathematical models specific to the data settings in LMIC’s impedes the construction of economic analysis necessary for decision-makers in the development of cancer control programs. This thesis presents a new methodology for parameterizing the natural history model of breast cancer based on data availabilities in low and middle income countries, and formulation of a control optimization problem to find the optimal screening schedule for mammography screening, solved using dynamic programming. As harms and benefits are known to increase with the …

Deubiquitinating Enzymes Promote Cancer Progression And Metastasis Via Regulating Protein Stability, Zhenna Xiao

Dissertations & Theses (Open Access)

Deubiquitinating enzymes (DUBs, also called deubiquitinases) are enzymes that remove monoubiquitin or polyubiquitin chains from target proteins. DUBs have critical roles in cell homeostasis and signal transduction, as they regulate protein degradation, subcellular localization, and protein-protein interaction. Deregulation of DUBs contributes substantially to tumor formation and progression, and therefore targeting DUBs may be a promising cancer therapy strategy. My dissertation focuses on identifying the DUBs of EZH2 and SNAI1, two proteins critical for cancer progression and metastasis, and establishing these DUBs as promising anti-cancer targets.

EZH2, the catalytic component of the PRC2 complex, silences gene transcription by histone methylation. High …

Gcn5 Loss Impacts Myc-Driven Cancer In Mice And Human Cells, Aimee Farria

Dissertations & Theses (Open Access)

GCN5 is the catalytic subunit in the acetyltransferase module of SAGA and ATAC, multiprotein complexes involved in the modification of histone and nonhistone proteins. GCN5 is most recognized as a co-activator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 where GCN5 acetylates H3K9 leading to a more open and accessible chromatin structure. Previous research has demonstrated that GCN5 also acetylates MYC, a protein that amplifies the expression of cancer-promoting genes and is frequently dysregulated in cancer, increasing its stability. Our lab has found there is a significant overlap in the …

Relationships Of Protein Biomarkers Of The Urokinase Plasminogen Activator System With Expression Of Their Cognate Genes In Primary Breast Carcinomas., Seth B. Sereff

College of Arts & Sciences Senior Honors Theses

Background: Urokinase plasminogen activator (uPA), its receptor uPAR and serine protease inhibitors PAI-1 or PAI-2 play key roles in tissue membrane remodeling and invasion of basement membranes by induction of a fibrinolytic pathway. Earlier studies reported that uPA and PAI-1 protein levels in breast carcinomas assist in prediction of response to chemotherapy. Our goal is to develop molecular signatures of candidate genes and identify novel relationships with these four protein biomarkers that demonstrate clinical utility for assessment of breast carcinoma outcomes.

Methods: This retrospective study used de-identified biomarker results and clinical outcomes from primary breast cancers that were stored in …

Synthetic Lectins, A Diagnostic And Prognostic Tool For Detecting Glycans In Breast Cancer, Daniel James Gordon

Theses and Dissertations

Cancer diagnostic tools have been pushed to the forefront of medical research because a person’s chance of survival is directly correlated with how early the tumor is identified and treatment is begun. In searching for the subtle differences between healthy and tumor cells, almost every type of cancer has been shown to under, over, or neo express glycans, and these changes in the glycan fingerprint can continue as the disease progresses. This provides a powerful diagnostic opportunity that’s works by screening for glycoproteins and glycosylation patterns that deviate from normal cells.

Boronic acids have a useful and tunable property in …

Brca1 And Brca2 Mutation Carrier Perspectives On Direct-To- Consumer Genetic Testing For Brca Mutations, Caitlyn E. Mitchell

Theses and Dissertations

Recently the FDA authorized one direct-to-consumer genetic testing (DTC-GT) company to begin reporting certain genetic variants in the BRCA1 and BRCA2 genes. Pathogenic variants in these genes confer lifetime risks for breast and ovarian cancer in women as high as 87% and 62%, respectively. Historically, genetic testing for these mutations has been offered in a clinical setting where genetic counseling is part of the testing process. Genetic counseling is not routinely a part of DTC-GT, raising concern that those undergoing DTC-GT for BRCA1/2 mutations may not fully understand what is being tested, the implications of results, or that they may …

Deciphering The Molecular Mechanism Through Which Rhus Coriaria Exerts Its Anti-Cancer Activity, Khawlah Najib Saeed Athamneh

Dissertations

Cancer remains a major health problem around the globe. Among various types of treatments, plants have been shown to have great capacity in cancer treatment, one of which is Rhus coriaria. Commonly known as sumac, Rhus coriaria is a culinary herb that is known to possess different therapeutic values including anti-oxidant and anti-microbial activities.

In this Ph.D. project, we tested the effect of Rhus coriaria extract (RCE) on the migration, invasion, and metastasis of MDA-MB-231 human breast cancer cells. We showed that non-cytotoxic concentrations of RCE inhibited migration and invasion, blocked adhesion to fibronectin, and downregulated MMP-9. Additionally, we found …

Impact Of Service Delivery Model On Patient Perceptions And Utility Of Genetic Counseling For Hereditary Breast And Ovarian Cancer: An Exploration Of Group Genetic Counseling, Alyssa M. Gates

Theses and Dissertations

Patients at risk for hereditary breast and ovarian cancer (HBOC) traditionally participate in individual cancer genetic counseling sessions to be educated about cancer genetics concepts, their personal cancer risks and genetic testing. With expanding technology and increased public awareness of HBOC, referrals to cancer genetic counseling services have grown. The current number of practicing genetic counselors struggles to meet the demands of increased referrals, so new service delivery models need to be explored. The purpose of this study is to assess the utility of group genetic counseling for HBOC by evaluating the perspectives of patients that received group genetic counseling …

Genetic Testing And The Power Of The Provider: Women’S Experiences With Cancer Genetic Testing, Dana Erin Ketcher

USF Tampa Graduate Theses and Dissertations

Genetic testing has become ubiquitous in contemporary society, from determining ancestry to addressing health concerns. This dissertation focused on a qualitative, feminist approach to understand women’s experiences of genetic testing for hereditary cancer syndromes, as well as their perspectives of risk. A total of 33 participants agreed to a semistructured interview and drawing of their family tree (pedigree). Eleven (40.7%) participants had been diagnosed with breast cancer, and 16 (59.3%) participants with ovarian cancer. Thirty-one (93.9%) participants had genetic testing, and of those, 17 (54.8%) had genetic counseling. Participants voiced several reasons why they wanted to undergo genetic testing or …

Utilizing Immunopet To Measure Tumor Response To Treatment In Breast Cancer, Brooke Mcknight

Wayne State University Dissertations

With a broad spectrum of therapies available for treating breast cancer, the need for personalized medicine tailoring the cure according to phenotype is evident. Such an approach may be fully realized with the development of quantitative imaging technologies for disease detection, staging and diagnosis, without increasing patient burden. Immuno-positron emission tomography (PET) combines the targeted specificity of antibodies with the sensitivity of PET for whole body imaging by targeting molecular features amplified in lesions. ImmunoPET probes targeting different antigens and their utility to measure response to treatment were explored. 89Zr-trastuzumab was employed as a surrogate readout of Src inhibition after …