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Pre-Clinical Trials With Precision-Medicine Based Therapeutics In Basal-Like Patient-Derived Xenografts, David C. Boyd
Pre-Clinical Trials With Precision-Medicine Based Therapeutics In Basal-Like Patient-Derived Xenografts, David C. Boyd
Theses and Dissertations
Breast cancer treatments have improved over time, but the diseases seeing the most benefit from these improvements have the estrogen receptor, progesterone receptor, or are positive for HER2. Basal-like breast cancer tends to not have these biomarkers, which necessitates their treatment to be traditional, untargeted therapeutics which are less effective and tend to have harsh adverse effect profiles – this is an important unmet need. These studies utilize a variety of techniques, including tissue culture, viability assays, high-throughput screening, in vivo drug treatments and imaging, pathway analyses, molecular techniques such as Western blot, antibody arrays, RNA sequencing, sc RNA sequencing, …
Kpt-330 Synergizes With Everolimus To Reduce Mtorc1-Overactive Basal-Like Triple-Negative Breast Cancer Brain Metastasis Burden, Aaron D. Valentine
Kpt-330 Synergizes With Everolimus To Reduce Mtorc1-Overactive Basal-Like Triple-Negative Breast Cancer Brain Metastasis Burden, Aaron D. Valentine
Theses and Dissertations
Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, accounts for approximately 20% of all breast cancer diagnoses. Basal-like TNBC is notably difficult to treat due to the lack of actionable drug targets such as estrogen and progesterone receptors, as well as HER2. Due to the deficiency in TNBC-targeting drugs that are able to cross the blood-brain barrier (BBB) for breast-to-brain metastasis, there is a need to develop novel BBB-permeable treatments. After preliminary testing, KPT-330 (XPO1 inhibitor) and everolimus (FKBP1A/mTOR inhibitor) were selected as drug candidates for this study. Patient-derived xenograft (PDX) models for in vitro and in vivo …
Prolactin Drives A Dynamic Stat5a/Hdac6/Hmgn2 Cis-Regulatory Landscape Exploitable In Er+ Breast Cancer, Justin M. Craig
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 …
The Human Intermediate Prolactin Receptor: A Breast Cancer Proto-Oncogene, Jacqueline M. Grible
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 …
Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch
Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch
Theses and Dissertations
The field of cancer research has grown immensely in recent decades and has led to a better understanding of the causes of the disease, as well as greatly improved treatment for various types of cancers, especially breast cancer. One of the most effective treatments involves the chemotherapeutic drug doxorubicin (DOX). DOX is an effective tool against all types of breast cancer, especially against triple negative breast cancer. However, DOX causes adverse side effects that include damage to the heart and skeletal muscle, particularly above specific cumulative doses. Recent evidence suggests that embryonic stem cell-derived (ES) exosomes, nanoscale extracellular vesicles that …
The Role Of Syndecan-1 And Extracellular Vesicles In Breast Cancer Brain Metastasis, Megan R. Sayyad
The Role Of Syndecan-1 And Extracellular Vesicles In Breast Cancer Brain Metastasis, Megan R. Sayyad
Theses and Dissertations
Breast cancer metastasizes to the brain in 15-30% of all breast cancer cases, and metastasis is the predominant cause of breast cancer-related deaths. Patients with HER2-enriched and triple-negative breast cancers (TNBCs) are more likely to develop brain metastases. While targeted therapies exist for HER2-enriched breast cancers, there are no effective treatments for TNBCs. Thus, a greater understanding of how these cancers spread to the brain is critical. In order to spread to the brain, disseminated breast cancer cells must overcome 2 major steps—crossing the blood-brain barrier (BBB) and survival and successful colonization of the distinctive and mostly cellular brain environment. …
Alternative Splicing Of Cytoplasmic Polyadenylation Element Binding Protein 2 Is Modulated Via Serine Arginine Splicing Factor 3 In Cancer Metastasis, James T. Deligio, James Thomas Deligio
Alternative Splicing Of Cytoplasmic Polyadenylation Element Binding Protein 2 Is Modulated Via Serine Arginine Splicing Factor 3 In Cancer Metastasis, James T. Deligio, James Thomas Deligio
Theses and Dissertations
Our laboratory delineated a role for alternative pre-mRNA splicing (AS) in triple negative breast cancer (TNBC). We found the translational regulator cytosolic polyadenylation element binding protein 2 (CPEB2) which has two isoforms, CPEB2A and CPEB2B, is alternatively spliced during acquisition of anoikis resistance (AnR) and metastasis. The splicing event which determines the CPEB2 isoform is via inclusion/ exclusion of exon four in the mature mRNA transcript. The loss of CPEB2A with a concomitant increase in CPEB2B is required for TNBC cells to metastasize in vivo. We examined RNAseq profiles of TNBC cells which had CPEB2 isoforms specifically downregulated to …
Sildenafil And Celecoxib Interact To Kill Breast Cancer Cells, Brittany Binion
Sildenafil And Celecoxib Interact To Kill Breast Cancer Cells, Brittany Binion
Theses and Dissertations
Breast cancer is the second most commonly diagnosed cancer among American women and is responsible for the second highest number of cancer-related deaths. Targeted therapeutic agents sildenafil, a phosphodiesterase type 5 inhibitor, and celecoxib, a cyclooxygenase-2 inhibitor, have been used individually in conjunction with other chemotherapeutic agents to enhance cell killing in a variety of cancers. Sildenafil when combined with traditional chemotherapeutic drugs, such as the taxanes and anthracyclines, or celecoxib combined with traditional hormone therapies have been used to increase cytotoxicity and cell killing. The data presented here demonstrates that the novel combination of sildenafil and celecoxib work together …
Acquired Epigenetic And Chromosomal Changes In Women Treated For Breast Cancer, Noran Aboalela
Acquired Epigenetic And Chromosomal Changes In Women Treated For Breast Cancer, Noran Aboalela
Theses and Dissertations
Improved survival for women receiving chemotherapy for breast cancer (BC) has been accompanied by the development/persistence of psychoneurological symptoms (PNS) that compromise their quality of life. The biological basis for these PNS is unknown, but could reflect the acquisition of soma-wide chromosomal/epigenetic alterations. An important first step in testing this hypothesis is to determine if somatic genetic/epigenetic changes arise and persist following treatment. To answer this question we longitudinally studied 71 women (ages 23-71) with early-stage BC and collected measures before chemotherapy (baseline), and 4 weeks (mid-chemo); six months (during radiation therapy for a subset of women); and one year …
Sorafenib Enhances Pemetrexed-Induced Cytotoxicity Through And Autophagy-Dependent Mechanism In Cancer Cells, Bareford Mary
Sorafenib Enhances Pemetrexed-Induced Cytotoxicity Through And Autophagy-Dependent Mechanism In Cancer Cells, Bareford Mary
Theses and Dissertations
Acquired cellular resistance to traditional chemotherapeutics is a common obstacle in the treatment of most cancer cell types. This resistance occurs as a result of changes in the underlying molecular mechanisms of disease progression. The development of novel chemotherapeutic approaches designed to enhance the efficacy of protypical anti-cancer drugs is important in order to overcome this issue. Such approaches will aid in understanding the biomolecular phenomena responsible for drug resistance and disease progression. Combining signaling pathway inhibitors has become an effective strategy for enhancing tumor cell death by targeting multiple pathways known to regulate cell survival. Pemetrexed, an FDA-approved anti-folate …
Crosstalk Between Lysophospatidic Acid (Lpa) And Transforming Growth Factor Beta (Tgfβ) In Breast And Ovarian Cancer Cells, Jinhua Wu
Theses and Dissertations
Lysophosphatidic acid (LPA) and transforming growth factor beta (TGFβ) are platelet-derived intercellular mediators of cell proliferation and motility. LPA is a general growth, survival and motility-stimulating factor in mammalian cells. TGFβ prevents proliferation of normal epithelial cells. However, the growth-inhibitory effect of TGFβ is lost or reduced in most malignant cells. Instead, TGFβ promotes migration and invasion of advanced cancer cells. Since LPA and TGFβ are both present in the blood and tumor microenvironments, we were interested in signal integration and functional outcomes in malignant epithelial cells in an LPA and TGFβ co-stimulatory context. In a subset of breast and …