The Role of Ceramide in Metastatic Processes in Breast Cancer
Open Access
- Author:
- Haakenson, Jeremy Kenneth
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 10, 2015
- Committee Members:
- Mark Kester, Dissertation Advisor/Co-Advisor
Mark Kester, Committee Chair/Co-Chair
Andrea Manni, Dissertation Advisor/Co-Advisor
Andrea Manni, Committee Chair/Co-Chair
Gary Alan Clawson, Committee Member
Cheng Dong, Committee Member
Rosalyn Bryson Irby, Committee Member - Keywords:
- ceramide
anoikis
metastasis
breast cancer
CD44
extravasation
carcinoma
epithelial-mesenchymal transition - Abstract:
- Ceramide is a bioactive sphingolipid that is capable of inducing apoptosis in mammalian cells. However, the role of ceramide in cancer metastasis remains largely unexplored. In this dissertation, I have demonstrated that ceramide induces anoikis, inhibits extravasation, and blocks the epithelial-mesenchymal transition (EMT) in metastasis-competent human breast cancer cell lines. Mechanistically, the effects of ceramide on anoikis and extravasation are mediated by lysosomal degradation of CD44, independent of palmitoylation or proteasome targeting. SiRNA down-regulation of CD44 mimics ceramide-induced anoikis and diminished extravasation of cancer cells. On the other hand, the ability of ceramide to prevent IL-6-induced EMT is dependent on its ability to inhibit STAT3 activation. Taken together, the data in this dissertation indicate that ceramide limits CD44-dependent breast cancer cell migration and IL-6/STAT3-dependent EMT, suggesting that ceramide analogs could be used to prevent and treat solid tumor metastasis.