Molecular Dissection of Breast Luminal Transcription Networks Public Deposited

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  • March 19, 2019
Creator
  • Bargiacchi, Francesca
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • During mammary development, cellular differentiation and lineage commitment to various epithelial and mesenchymal cell types are driven by hormonal and paracrine signaling mechanisms. Understanding mechanisms that govern differentiation into distinct cell populations is critically important for a complete understanding of development and breast tumorigenesis. Previous studies have shown that retroviral transduction of fibroblasts with four transcription factors can initiate the conversion of a somatic cell into an embryonic stem cell-like state with capabilities of differentiating into cell types of all three germ layers. The goal of my thesis work was to determine whether mammary specific transcription factors (TFs) could directly induce transdifferentiation to an ER+/luminal cell phenotype starting with mouse embryonic fibroblasts via an iPS-type approach. After screening 9 candidate TFs for their abilities to induce various epithelial-specific and breast-specific attributes, we focused subsequent efforts on ESR1, FOXA1, PGR, and GATA3. In human mammary epithelial cells, ectopic overexpression of these TFs had both unique and overlapping contributions toward inducing the expression of genes responsible for luminal differentiation. Combining these TFs in fibroblasts created combinations that produced a luminal progenitor phenotype as defined by gene expression histological markers for epithelial/breast development and functionality. Examination of the gene expression patterns induced by these combinations using a classifier of differentiation status identified several genes that drive a transition toward the luminal subtype. Since there are presently no cell lines or mouse models of luminal A/ER+ breast cancers, the creation of such of a line would be of tremendous value.
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  • In Copyright
Advisor
  • Earp, H. Shelton
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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Place of publication
  • Chapel Hill, NC
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