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
  • Mark Kester, Committee Chair
  • Andrea Manni, Dissertation Advisor
  • Andrea Manni, Committee 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.