Disruption of normal mammary epithelial cell homeostasis through acquisition of deleterious somatic and/or germline mutations leads to breast cancer development. Breast cancer is the most commonly diagnosed cancer among women worldwide, and is associated with the second highest amount of cancer-related deaths. Breast cancer mortality rates are decreasing, likely through increased methods of detection and development of targeted therapies. However, due to the complexity and heterogeneity of the disease, the incidence rate remains high and the molecular events that lead to breast cancer initiation and progression are poorly understood. The epithelial-to-mesenchymal transition (EMT) is an essential molecular process involved in the initiation and progression of epithelial-based tumors. Loss of cell-cell connections, altered extracellular matrix interactions, and dramatic cytoskeletal changes promote cell individuality and development of a migratory and often invasive phenotype. Under normal physiological conditions, EMT is involved in processes such as embryonic development and wound healing. EMT is tightly regulated by a combination of signaling pathways and epigenetic factors. However, the molecular mechanisms that suppress EMT within the normal epithelium to prevent tumorigenesis remain understudied. Mitotic gene bookmarking -- retention of cell lineage-specific transcription factors with target genes, together with histone modifications, specific DNA methylation patterns, and components of transcriptional machinery on mitotic chromosomes -- is an epigenetic mechanism that maintains cellular identity throughout successive cell divisions. Mitotic occupancy and post-mitotic transcription regulation of target genes involved in proliferation, growth, and cellular identity by transcription factors, reestablishes epithelial-specific transcriptional programs in newly formed progeny cells. The RUNX1-CBF[Beta] heterodimeric transcription factor complex is essential for normal mammary gland development. Mutations in both subunits have been identified in breast cancers. Studies by our group have shown that RUNX proteins act as mitotic bookmarks in a variety of tissue types and depletion of RUNX1 in normal mammary epithelial cells leads to EMT. Findings reported in this study show that inhibition of the RUNX1-CBF[Beta] interaction disrupts the normal mammary epithelial phenotype, alters cell cycle regulation, and initiates EMT. Furthermore, results demonstrate RUNX1 is maintained on mitotic chromosomes during all topologically identifiable stages of mitosis in live MCF10A cells. Conditions and methods have been optimized to study the specific function of the RUNX1-CBF[Beta] transcription factor complex as a mitotic bookmark, essential for mitotic and post-mitotic transcriptional regulation of genes involved in proliferation, cell growth, and epithelial cell identity throughout successive cell divisions. Further studies utilizing these conditions and methods are required to address the functional role of the RUNX1-CBF[Beta] transcription factor complex as an essential mitotic bookmark involved in phenotypic maintenance in the normal mammary epithelium.

Breast cancer arises from a series of acquired mutations that disrupt normal mammary epithelial homeostasis and create multi-potent cancer stem cells that can differentiate into clinically distinct breast cancer subtypes. Despite improved therapies and advances in early detection, breast cancer remains the leading diagnosed cancer in women. A predominant mechanism initiating invasion and migration for a variety of cancers including breast, is epithelial-to-mesenchymal transition (EMT). EMT-- a trans-differentiation process through which mammary epithelial cells acquire a more aggressive mesenchymal phenotype--is a regulated process during early mammary gland development and involves many transcription factors involved in cell lineage commitment, proliferation, and growth. Despite accumulating evidence for a broad understanding of EMT regulation, the mechanism(s) by which mammary epithelial cells maintain their phenotype is unknown. Mitotic gene bookmarking, i.e., transcription factor binding to target genes during mitosis for post mitotic regulation, is a key epigenetic mechanism to convey regulatory information for cell proliferation, growth, and identity through successive cell divisions. Many phenotypic transcription factors, including the hematopoietic Runt Related Transcription Factor 1 (RUNX1/AML1), bookmark target genes during mitosis. Despite growing evidence, a role for mitotic gene bookmarking in maintaining mammary epithelial phenotype has not been investigated. RUNX1 has been recently identified to play key roles in breast cancer development and progression. Importantly, RUNX1 stabilizes the normal breast epithelial phenotype and prevents EMT through repression of EMT-initiating pathways. Findings reported in this thesis demonstrate that RUNX1 mitotically bookmarks both RNA Pol I and II transcribed genes involved in proliferation, growth, and mammary epithelial phenotype maintenance. Inhibition of RUNX1 DNA binding by a specific small molecule inhibitor led to phenotypic changes, apoptosis, differences in global protein synthesis, and differential expression of ribosomal RNA as well as protein coding genes and long non-coding RNA genes involved in cellular phenotype. Together these findings reveal a novel epigenetic regulatory role of RUNX1 in normal-like breast epithelial cells and strongly suggest that mitotic bookmarking of target genes by RUNX1 is required to maintain breast epithelial phenotype. Disruption of RUNX1 bookmarking results in initiation of epithelial to mesenchymal transition, an essential first step in the onset of breast cancer.

While the transformation of cancer cells through epigenetic modifications has been recognized for some time, recent advances in genome-wide genomic and epigenomic sequencing has revealed the extensive presence of mutations in epigenetic regulators and the comprehensive scope of epigenomic changes in cancer cells. It is now evident that genetic and epigenetic mechanisms are not mutually exclusive and work in tandem to facilitate the acquisition of the characteristic traits of cancer.Mitosis plays a pivotal role in transmitting lineage specific transcriptional control, imparting phenotypic memory and determination of cell fate. Nuclear organization and three-dimensional architecture of the genome is disrupted during mitosis, yet daughter cells preserve their gene expression patterns and phenotypic state. During mitosis most transcription factors dissociate from promoter sequences as well as from bulk chromatin. However, around 20% of transcription factors and chromatin binding proteins are retained at their specific target sites. Retention of the RUNX1 tumor suppressor with target gene loci on mitotic chromosomes during cell division, a process we designate "Mitotic gene bookmarking," which epigenetically sustains competency for gene expression during cell division. In this study, we are investigating the role of RUNX1 in maintaining the epithelial phenotype and its loss in transformation to the mesenchymal phenotype using degron technology, targeting the RUNX1 factor for rapid degradation, to directly establish the requirement for this tumor suppressor to sustain gene expression that is obligatory for physiological control of normal and tumor phenotypes. By combing the expression profiles of mature RNA and nascent transcript analysis we were able to measure rapid changes in the core of RUNX1 regulatory network and obtain a list of differentially expressed genes. Furthermore, loss of RUNX1 results in the emergence of a heterogenous population of cells that are resistant to apoptosis and undergo a transition between cellular states exhibiting partial EMT and phenotypic plasticity.

Introducing an essential new practical atlas for dental students and clinicians alike! The Color Atlas of Oral and Maxillofacial Diseases provides comprehensive, practical information on the most common oral and maxillofacial diseases and disorders. This new text uses a quick-access atlas format to help you easily look up clinical signs, diagnosis, and treatments. Nearly 750 high-quality images accompanied by brief narratives demonstrate exactly what clinical signs to look for – making an intervention as timely as possible. Written by four of the top dental authorities in the world, this concise resource is sure to become a clinical favorite. NEW! Quick-access atlas format makes it easy to look up clinical signs, diagnosis, and treatment of oral and maxillofacial diseases NEW! Nearly 750 high-quality radiographs and color clinical photos facilitate the identification of lesions and diseases. NEW! Comprehensive, focused coverage highlight diseases that may affect the oral and maxillofacial regions. NEW! Full-color design and illustrations. NEW! Logical organization reflects the sequence in which content is generally presented to predoctoral students

Gradients and Tissue Patterning, Volume 137 in the Current Topics in Developmental Biology series, highlights new advances in the field, with this new volume presenting interesting chapters on a variety of timely topics. Each chapter is written by an international board of authors.

Unlike anything currently available in the market, Dr. Sally A. Moody and a team of world-renowned experts provide a groundbreaking view of developmental genetics that will influence scientific approaches in embryology, comparative biology, as well as the newly emerging fields of stem cell biology and regenerative medicine. Principles of Developmental Genetics highlights the intersection of developmental biology with new revolutionary genomic technologies, and details how these advances have accelerated our understanding of the molecular genetic processes that regulates development. This definitive resource provides researchers with the opportunity to gain important insights into the clinical applicability of emerging new technologies and animal model data. This book is a must-have for all researchers in genetics, developmental biology, regenerative medicine, and stem cell biology. • Includes new research not previously published in any other book on the molecular genetic processes that regulates development • Chapters present a broad understanding on the application of animal model systems, allowing researchers to better treat clinical disorders and comprehend human development • Relates the application of new technologies to the manipulation of stem cells, causes of human birth defects, and several human disease conditions • Each chapter includes a bulleted summary highlighting clinical aspects of animal models

This book is a compilation of high-yield, at-a-glance summaries for various topics on which pathologists frequently need information in a quick reference format while at the microscope (or when cramming for the boards). The authors are early-career pathologists who have compiled this book from the perspective of pathologists-in-training. The focus is not organ-based histologic criteria, but rather everything else that goes into pathologic diagnoses but is difficult to keep committed to memory. The emphasis is on immunohistochemistry, special stains, grading systems, molecular markers, tumor syndromes, and helpful clinical references. The book has a unique format in that the information is presented primarily in tables and diagrams accompanied by minimal explanatory text. It is intended to serve as a ‘peripheral brain’ for pathology residents and also practicing pathologists, where frequently needed information is readily accessible and easy to navigate.