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      • HARVEST
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      Investigation of S1P and S1P Signaling in Adipocytes and Adipocyte-Breast Cancer Cell Interaction

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      WU-THESIS-2021.pdf (4.583Mb)
      Thesis-Xiyuan Wu - Final V2, Jan 2021. .pdf (5.191Mb)
      Date
      2021-01-22
      Author
      Wu, Sharon
      ORCID
      0000-0002-8206-1071
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      Breast cancer continues to be the most commonly occurring cancer in women worldwide, with triple-negative breast cancer (TNBC) as the most aggressive subtype with a high risk of metastasis and recurrence. Obesity is one of the factors that increase breast cancer risk and progression, and high accumulation of adipocytes is increasingly recognized as an active facilitator in the interaction between the tumor and the adipose tissue in the breast. Adipocytes may act as a therapeutic obstacle and can be viewed as a target in breast cancer, as they affect tumor initiation, progression, invasion, and metastasis by changing their genetic signature and/or the secretion of different adipokines/adipocytokines. Sphingosine-1-phosphate (S1P) is the final product of sphingolipid metabolism, affecting proliferation, apoptosis, inflammation, and angiogenesis. Common therapeutic strategies for targeting S1P in cancers showed little successful progress. In contrast, data have shown the pro-apoptotic and anti-proliferation effect of S1P on breast cancer cells, with higher efficiency against aggressive breast cancer cells (i.e., TNBC cells). Thus, S1P could be a potential drug candidate for breast cancer treatment. This study examined S1P’s regulation on functional and transcriptional activities in adipocytes. The anti-cancer effect of S1P on breast cancer cells in an adipocyte-derived microenvironment, as well as potential roles of the S1P signaling, were also explored. Results showed that S1P had a stimulatory effect on pre-adipocyte but an inhibitory effect on differentiated adipocyte cell viability. Suppression of lipid accumulation during adipogenic differentiation was observed. These effects might be explained by the transcriptome analysis, which indicated the involvement of cell cycle, G-protein coupled receptor pathways, and the regulation of lipid metabolism processes. At high nM to low μM concentrations, S1P was observed to impose its anti-cancer effects on TNBC cells, and the effectiveness was influenced by adipocyte-derived conditions. These findings demonstrated that the potential mechanism of S1P in suppressing breast cancer cell growth could be through altering adipocyte metabolism and breaking the crosstalk between breast adipocytes and cancer cells. This study provides possibilities to identify adipocytes in the breast as effective therapeutic targets and develop potential treatments for TNBC.
      Degree
      Master of Science (M.Sc.)
      Department
      Pharmacy and Nutrition
      Program
      Pharmacy
      Supervisor
      Yang, Jian
      Committee
      Meena, Sakharkar; Brian, Bandy; Krol, Ed; Uppalapati, Maruti Chandra
      Copyright Date
      January 2021
      URI
      http://hdl.handle.net/10388/13222
      Subject
      Sphingosine-1-phosphate
      adipocytes
      breast cancer
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