RNA splicing in breast cancer progression

Koedoot, E. (2019)

Doctoral Thesis

In this thesis, we aimed to better understand the underlying mechanisms involved in TNBC progression and metastasis formation and discover new targets to reduce breast cancer related deaths. We performed an imaging-based RNAi phenotypic cell migration screen in two highly motile TNBC cancer cell lines to provide a repository of signaling determinants that functionally drive TNBC cell motility. Interestingly, two modulators essential for cancer cell migration were known to be involved in RNA splicing, making us decide to focus on the role of RNA splicing in breast cancer progression. We next summarized the current knowledge about splicing factors in breast cancer development and progression and identified co-regulated splicing factors that were associated with aggressive breast cancer phenotypes and metastasis formation that was not only restricted to breast cancer, increasing the global understanding of the role of the spliceosome in cancer development and progression. Moreover, the role of splicing factors in two major processes in cancer progression, cell migration and proliferation, was examined. Finally, using RNA sequencing, we systematically compared the transcriptomes of 14 breast cancer cell lines cultured both in 2D and 3D conditions to unravel the reprogramming that is associated with the invasive phenotype of basal B TNBC.

• Breast cancer
• RNA splicing
• siRNA screening
• Transcriptomics

• All authors: Koedoot, E.
• Supervisor: Water, B. van de
• Co-supervisor: Le Dévédect, S.E.
• Committee: Irth, H.; Bouwstra, J.A.; Martens, J.W.M.; Sonnenberg, A.; Dijke, P. ten; Snaar-Jagalska, B.E.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drugs Research (LACDR), Faculty of Science, Leiden University
• Date: 2019-12-17
• ISBN (print): 9789402817447