Dissertation
Role of transcription factor activator protein 2C in mammary gland development and carcinogenesis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2020
DOI: 10.17077/etd.005601
Abstract
Mammary gland development depends on differentiation of mammary stem cells to form a mature mammary gland. Neoplasms can arise when this process is dysregulated. The AP-2γ transcription factor, encoded by the TFAP2C gene (Tfap2c for the mouse gene), has been shown to be critical for mammary development and can contribute to breast cancer pathogenesis.
The first part of this thesis focuses on the role of TFAP2C in HER2-amplified breast cancer. Previous studies have shown that HER2-amplified breast cancer exhibit a strong genetic dependency on TFAP2C. However, little is known about the mechanisms involved. We hypothesize that TFAP2C plays an important role in HER2-amplified breast cancer through regulation of critical gene targets involved in tumorigenesis and progression. To test this hypothesis, we developed a tissue specific Tfap2c knockout in mice. We showed that loss of Tfap2c decreased tumor incidence and increased tumor free survival in a murine model of HER2-amplified breast cancer and identified Egfr as a key Tfap2c target gene.
The second part of this thesis focuses on the role of TFAP2C in mammary development. AP-2γ has been shown to regulate mammary development but the precise mechanisms remain unclear. We aimed to elucidate the role of AP-2γ in mammary stem cell (MaSC) self-renewal and differentiation. Using a genetic mouse model, we eliminated Tfap2c in the basal epithelial layer where MaSCs reside and found that loss of Tfap2c inhibited mammary tree branching and maturation. Additionally, single-cell RNA sequencing (scRNA-seq) showed transcriptomic alterations in different mammary cell lineages and demonstrated that TFAP2C is required for MaSC self-renewal and differentiation.
These studies significantly advance the understanding of the mechanisms of gene regulation and critical pathways through which AP-2γ regulates mammary gland development and cancer growth
Details
- Title: Subtitle
- Role of transcription factor activator protein 2C in mammary gland development and carcinogenesis
- Creators
- Vivian Wu Gu
- Contributors
- Ronald J Weigel (Advisor)Mark A Stamnes (Committee Member)Michael D Henry (Committee Member)Michael E Wright (Committee Member)Weizhou Zhang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Molecular Physiology and Biophysics
- Date degree season
- Summer 2020
- DOI
- 10.17077/etd.005601
- Publisher
- University of Iowa
- Number of pages
- xiv, 115 pages
- Copyright
- Copyright 2020 Vivian Wu Gu
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 104-115).
- Public Abstract (ETD)
Normal mammary gland development is a complex process that involves cellular proliferation and differentiation. Disruption of this process can initiate tumor development. However, a better understanding of the molecular mechanisms and factors that regulate mammary gland development and breast cancer tumorigenesis is needed. Transcription factor AP-2ɣ is a regulatory protein that has been implicated in the control of proliferation, differentiation, and apoptosis pathways. HER2-enriched breast cancer has traditionally been associated with an aggressive disease course and has been shown to correlate with AP-2ɣ levels. The aim of this thesis is to provide a comprehensive analysis of the regulatory role of AP-2ɣ gene targets and pathways in mammary gland development and breast cancer initiation and growth. We will use various genetically modified mice, cultured cancer cells, and sequencing analysis of normal mammary gland as well as breast carcinomas to study the factors involved in mammary development and breast cancer.
- Academic Unit
- Molecular Physiology and Biophysics
- Record Identifier
- 9983988099402771
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