Cancer Biology Commons^™

An Investigation Of Epigenetic Mechanisms Driving The Biology Of Head And Neck Squamous Cell Carcinoma, Scot Carson Callahan

Dissertations & Theses (Open Access)

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and is associated with significant morbidity and mortality. To date, the majority of work in the field has focused on genomic alterations such as mutations and copy number alterations. However, the clinical success of targeted therapies that exploit known genomic alterations, such as EGFR mutations, has remained mixed. Over the past decade, the importance of epigenetic regulators has come to the forefront, with the realization that many of these genes are mutated in cancer. Despite this realization, the role of epigenetics in regulating tumorigenesis, progression and …

10th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

Annual Postdoctoral Science Symposium Abstracts

The Annual Postdoctoral Science Symposium (APSS) was initiated on August 4, 2011, by the MD Anderson Postdoctoral Association to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience.

APSS is a scientific symposium organized by postdoctoral fellows from The University of Texas MD Anderson Cancer Center that welcomes submissions and presentations from postdoctoral fellows from all Texas Medical Center affiliated institutions and other Houston area institutions. The APSS provides a professional venue for postdoctoral scientists to develop, clarify and refine their research as result of formal reviews and critiques …

Grainyhead-Like 2 Sensitizes Cells To Natural Killer Cell Cytotoxicity And Promotes The Interferon Response, Ian Philip Macfawn

Graduate Theses, Dissertations, and Problem Reports

Our research determined that the epithelial master transcription factor Grainyhead-like 2 (GRHL2) promotes sensitivity to Natural Killer (NK) cell-mediated killing, and modulates the interferon I (IFN-I) response of epithelial cells. Immune surveillance by NK cells constitutes a major selective pressure for circulating tumor cells. Epithelial (GRHL2-expressing) cells exhibited significantly higher rates of NK conjugation, a crucial step in direct cell-mediated cytotoxicity. Mechanistically, GRHL2 upregulates expression of intercellular adhesion molecule 1 (ICAM-1), a cell surface molecule critical for NK to target cell synaptogenesis. GRHL2 epigenetically regulates gene expression, and we found that GRHL2 mutant proteins unable to interact with the epigenetic …

9th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

Annual Postdoctoral Science Symposium Abstracts

The mission of the Annual Postdoctoral Science Symposium (APSS) is to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience. The MD Anderson Postdoctoral Association convened its inaugural Annual Postdoctoral Science Symposium (APSS) on August 4, 2011.

The APSS provides a professional venue for postdoctoral scientists to develop, clarify, and refine their research as a result of formal reviews and critiques of faculty and other postdoctoral scientists. Additionally, attendees discuss current research on a broad range of subjects while promoting academic interactions and enrichment and developing new collaborations.

Characterization Of A More Clinically Relevant Human Leukemia Xenograft Model To Examine Perturbation Of Met/Sam Metabolism As A Novel Therapeutic Paradigm For Mll-R Leukemia In Vivo., Aditya Barve

Electronic Theses and Dissertations

Acute myeloid leukemia (AML), is a heterogeneous clonal disorder characterized by an accumulation of malignant myeloid progenitors in the bone marrow (BM), hindering normal hematopoiesis. AML exhibits dramatic heterogeneity in terms of cytogenetics, morphology, and chemotherapeutic sensitivity. Therefore, the investigation of novel, efficacious AML therapeutics will require advanced preclinical in vivo model systems, capable of recapitulating patient specific disease heterogeneity, and induction chemotherapy outcomes. A major focus and eventual outcome of this work was the establishment and development of a more clinically relevant mouse xenograft model of patient AML, that efficiently harbors patient derived xenografts (PDXs), and unlike more prevalent …

Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue

Dissertations & Theses (Open Access)

Transcription is strictly regulated by numerous factors including transcription coactivators. The p300 protein and its close paralogue CREB-binding protein (CREBBP, aka CBP) are well-known transcriptional coactivators that have intrinsic lysine acetyltransferase activity. The functions of p300/CBP largely rely on their capabilities to bind to chromatin and to acetylate the histone substrates. However, the molecular mechanisms underlying the regulation of these processes are not fully understood.

Through combination of various biochemical, biophysical and molecular approaches, we show that the ZZ-type zinc finger (ZZ) domain of p300 functions as a histone reader that specifically binds the N-terminal tail of histone H3. Crystal …

Trim24 As An Oncogene In The Mammary Gland, Aundrietta Duncan

Dissertations & Theses (Open Access)

Despite the many advances made in breast cancer research and treatments, breast cancer remains one of the deadliest diseases plaguing women worldwide. While many findings on genetic mutations and their role in predisposing people to breast cancer have been uncovered, we are just beginning to understand the extent to which epigenetic regulators promote tumorigenic phenotypes, metastasis, and chemotherapeutic resistance. Moreover, new experimental tools offer the ability to address questions we were previously unable to assess. My project takes advantage of a new mouse model to understand the role of a proto-oncogenic, transcriptional co-regulator, TRIM24, in mammary gland development and disease. …

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

Dissertations & Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is …

The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers

Electronic Theses and Dissertations

Primordial germ cells (PGCs) are hypothesized to deposit hematopoietic stem cells (HSCs) along their migration route through the embryo during the early stages of embryogenesis. PGCs also undergo global chromatin remodeling, including the erasure and reestablishment of genomic imprints, during this migration. While PGCs do not spontaneously form teratomas, their malignant development into germ cell tumors (GCTs) in vivo is often accompanied by the retention of hypomethylation at the IGF2-H19 imprinting control differentially methylated region (DMR). Previous studies in bimaternal embryos determined that proper genomic imprinting at two paternally imprinted loci was necessary for their growth and development: Igf2-H19 and …

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

Dissertations & Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important …

Nanobubbles Provide Theranostic Relief To Cancer Hypoxia, Christopher M. Long, Pushpak N. Bhandari, Joseph Irudayaraj

The Summer Undergraduate Research Fellowship (SURF) Symposium

Hypoxia is a common motif among tumors, contributing to metastasis, angiogenesis, cellular epigenetic abnormality, and resistance to cancer therapy. Hypoxia also plays a pivotal role in oncological studies, where it can be used as a principal target for new anti-cancer therapeutic methods. Oxygen nanobubbles were designed in an effort to target the hypoxic tumor regions, thus interrupting the hypoxia-inducible factor-1α (HIF-1α) regulatory pathway and inhibiting tumor progression. At less than 100nm, oxygen nanobubbles act as a vehicle for site-specific oxygen delivery, while also serving as an ultrasound contrast agent for advanced imaging purposes. Through in vitro and in vivo studies, …

Inhibition Of Dna Methylation In Acquired Tamoxifen-Resistant Breast Cancer: Cell Line Model And Clinical Implications, Stephanie Zimmers

Doctoral Dissertations

One out of every eight American women will develop invasive breast cancer throughout their lifetime. Approximately 70% of breast cancers are estrogen receptor alpha (ER)-positive and can therefore be treated with an anti-estrogen such as tamoxifen. Although tamoxifen treatment has been successful at reducing breast cancer death rates, nearly one-third of women treated with tamoxifen for 5 years will have disease recurrence. Therefore, it is imperative that researchers investigate the mechanisms involved in developing acquired tamoxifen resistance and identify biomarkers that are predictive of acquired resistance. DNA methylation is known to play a role in the development of breast cancer …

Dna-Based Epigenetic Changes In Recurrent And Tamoxifen-Resistant Breast Cancer, Kristin E. Williams

Doctoral Dissertations

Roughly two-thirds of all breast cancers are Estrogen Receptor a (ER)-positive and can be treated with an anti-estrogen such as Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 years. In addition to this acquired antiestrogen resistance, de novo- or intrinsic-resistance occurs primarily in ER-negative tumors but also occasionally in ER-positive tumors. Aberrant DNA promoter methylation, a major epigenetic mechanism by which gene expression is altered in cancer, is thought to play a role in this resistance. To date, few studies have examined promoter methylation and Tamoxifen resistance in breast cancer. Of the …

The Role Of Dna Methyltransferases In Normal And Malignant Hematopoiesis, Staci Haney

Theses & Dissertations

DNA methylation is an epigenetic modification that regulates gene transcription. The addition of a methyl group to cytosine is catalyzed by a family of enzymes known as DNA methyltransferases (Dnmts). The three catalytically active Dnmts in humans and mice are Dnmt1, Dnmt3a, and Dnmt3b. DNA methylation is clinically relevant, as aberrations in the methylation landscape are a hallmark of nearly all human cancers. Cancer methylomes are typically characterized by genome wide hypomethylation and regional specific hypermethylation, both of which have been linked to alterations in gene expression. In order to understand the contribution of epimutations to the development of hematological …

Understanding Ten-Eleven Translocation-2 In Hematological And Nervous Systems, Feng Pan

FIU Electronic Theses and Dissertations

I proposed the study of two distinct aspects of Ten-Eleven Translocation 2 (TET2) protein for understanding specific functions in different body systems.

In Part I, I characterized the molecular mechanisms of Tet2 in the hematological system. As the second member of Ten-Eleven Translocation protein family, TET2 is frequently mutated in leukemic patients. Previous studies have shown that the TET2 mutations frequently occur in 20% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% T-cell lymphoma leukemia and 2% B-cell lymphoma leukemia. Genetic mouse models also display distinct phenotypes of various types of hematological malignancies. I performed 5-hydroxymethylcytosine (5hmC) chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA …

Characterization Of The Anti-Apoptotic Function Of The Lysine Demethylase Plant Homeodomain Finger Protein 8 (Phf8), Kimberly Muranko

Electronic Thesis and Dissertation Repository

Apoptosis is an essential process in development and tissue maintenance. The tumor suppressor protein p53 initiates apoptosis through transactivation of pro-apoptotic genes when cellular stress is detected. This study identifies a regulatory role for the lysine demethylase, PHF8, in the p53-mediated apoptosis pathway. We initially suspected PHF8 of demethylating the adaptor protein Numb, however found this to be untrue. PHF8 has been found to have oncogenic properties including an anti-apoptotic effect, however how PHF8 negatively affects apoptosis has not been previously investigated. We found PHF8 inhibits translation of the pro-apoptotic genes TP53, BAX and CASP3. Chromatin immunoprecipitation revealed …

Trim24-Regulated Estrogen Response Is Dependent On Specific Histone Modifications In Breast Cancer Cells, Teresa T. Yiu

Dissertations & Theses (Open Access)

In this dissertation, I discovered that function of TRIM24 as a co-activator

of ERα-mediated transcriptional activation is dependent on specific histone

modifications in tumorigenic human breast cancer-derived MCF7 cells. In the first

part, I proved that TRIM24-PHD finger domain, which recognizes unmethylated

histone H3 lysine K4 (H3K4me0), is critical for ERα-regulated transcription.

Therefore, when LSD1-mediated demethylation of H3K4 is inhibited, activation of

TRIM24-regulated ERα target genes is greatly impaired. Importantly, I

demonstrated that TRIM24 and LSD1 are cyclically recruited to estrogen

responsive elements (EREs) in a time-dependent manner upon estrogen

induction, and depletion of their expression exert corresponding time-dependent

effect …

The Linkage Between Transcription Control And Epigenetic Regulation: The Snail Story And Beyond, Yiwei Lin

Theses and Dissertations--Pharmacology and Nutritional Sciences

Epigenetic deregulation contributes significantly to the development of multiple human diseases, including cancer. While great effort has been made to elucidate the underlying mechanism, our knowledge on epigenetic regulation is still fragmentary, an important gap being how the diverse epigenetic events coordinate to control gene transcription. In the first part of our study, we demonstrated an important link between Snail-mediated transcriptional control and epigenetic regulation during cancer development. Specifically, we found that the highly conserved SNAG domain of Snail sequentially and structurally mimics the N-terminal tail of histone H3, thereby functions as a molecular “hook”, or pseudo substrate, for recruiting …

Xenoestrogen-Specific Mechanisms Of Developmental Reprogramming Correlate With Gene Expression And Tumor Development, Kristen L. Greathouse

Dissertations & Theses (Open Access)

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. We have shown that neonatal exposure to the xenoestrogen diethylstilbestrol (DES) can developmentally reprogram the reproductive tract in genetically susceptible Eker rats giving rise to complete penetrance of uterine leiomyoma. Based on this, we hypothesized that xenoestrogens, including genistein (GEN) and bisphenol A (BPA), reprogram estrogen-responsive gene expression in the myometrium and promote the development of uterine leiomyoma. We proposed the mechanism that is responsible for the developmental reprogramming of gene expression was through …