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Thesis
The role of KLF8 in breast cancer stem cells
Master of Science (M.S.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000847
Abstract
Breast tumors are comprised of heterogenous cell populations. This intra-tumor heterogeneity drives tumor-initiation, metastasis, and resistance to anti-cancer treatments, potentially by a subpopulation of tumor cells, called cancer stem-like cells (CSCs). CSCs share properties of adult stem cells and correlate with poor patient outcomes. The hexosamine biosynthetic pathway (HBP), a nutrient-sensing pathway, links metabolism and cell signaling in cancer cells. HBP final product, UDP-GlcNAc, is used by the O-GlcNAc transferase enzyme (OGT) as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins. Recently, we reported that OGT/O-GlcNAc promote breast tumor-initiation and increase breast CSC populations. We also showed that Krüppel-like factor 8 (KLF8), a transcription factor associated with invasion and metastasis, is a downstream effector of OGT in CSCs. Here, we show that KLF8 is critical in regulating CSCs and chemo-resistance in breast cancer cells. Overexpression of KLF8 in breast cancer cells increased mammosphere-forming efficiency, ALDH+, and Nanog-GFP+ CSC populations. Consistently, genetically targeting KLF8 expression in breast cancer cells decreased the CSC-enriched population and expression of CSC markers including SOX2, OCT4, NANOG, c-MYC. Interestingly, KLF8 also regulates RNA and protein levels of OGT in breast cancer cells suggesting a feedforward loop. Importantly, KLF8 overexpression impaired paclitaxel-mediated apoptosis in breast cancer cells. Together, our data shows a novel role of KLF8 in regulating breast cancer stem-like cell populations, and chemoresistance, and suggests that OGT and KLF8 may co-regulate each other to increase breast cancer stem cells and to promote drug resistance.
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Details
- Title
- The role of KLF8 in breast cancer stem cells
- Creators
- Tejsi Tulsibhai Dhameliya
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 44 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991015273171604721