Date of Award
Master of Science (MS)
Jonathan A. Gordon
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-CBFβ 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-CBFβ 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-CBFβ 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-CBFβ transcription factor complex as an essential mitotic
bookmark involved in phenotypic maintenance in the normal mammary epithelium.
Number of Pages
Moskovitz, Eliana, "Investigating The Runx1-Cbfβ Transcription Factor Complex As A Mitotic Gene Bookmark To Maintain The Normal Mammary Epithelial Phenotype" (2020). Graduate College Dissertations and Theses. 1286.