Volume 8 Supplement 2
Loss of C-terminal binding protein transcriptional corepressor leads to aberrant mitosis and cell death in breast cancer cells
© BioMed Central Ltd 2006
Published: 01 November 2006
C-terminal binding proteins (CtBPs) are transcriptional corepressors that regulate the activity of proteins important for a wide variety of cellular processes, including development, proliferation, differentiation, and transformation. Many targets of CtBP corepression are members of pathways involved in tumorigenesis, and evidence is emerging that CtBPs also play a role in cell survival. Loss of CtBP in different experimental systems leads to upregulated expression of a number of proapoptotic genes and increased sensitivity to apoptosis.
In this study, we have continued investigation into the role of CtBPs in breast cancer cell survival, identifying a previously unknown function for CtBPs in the regulation of the mitotic spindle checkpoint. Loss of CtBP expression by RNAi results in a marked decrease in cell number, and in reduced cell viability and clonogenicity. We find that this apparent cell death does not occur by a traditional caspase-mediated apoptotic pathway.
Detailed microscopic analysis of the morphology of MCF7 breast cancer cells lacking CtBPs reveals an increase in the number of cells containing abnormal micronucleated cells and dividing cells with lagging chromosomes, indicative of aberrant mitotic chromosomal segregation. Live cell imaging reveals defects in cell abcission after mitosis following CtBP knockdown. Furthermore, cells lacking CtBP fail to undergo mitotic arrest induced by spindle toxins, indicating a spindle checkpoint defect. The loss of cell viability in breast cancer cells following CtBP inhibition is most probably a consequence of aberrant mitosis and cell death by mitotic catastrophe. Here we present a detailed characterization of the mechanism by which CtBPs are involved in mitosis and cell survival, which we hope will increase our understanding of how breast cancer cells evade cell death, and ultimately lead to new treatments for patients.
This research was funded by Breast Cancer Campaign.