Abstract
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.
Highlights
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis
We have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk
No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects
Summary
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis. BRCA1 is a tumour suppressor gene which is mutated in up to 5–10% of breast cancer cases and is involved in multiple cellular processes including DNA damage control, cell cycle checkpoint control, apoptosis, ubiquitination and transcriptional regulation. Results We have previously carried out microarray-based expression profiling to examine differences in gene expression when BRCA1 is reconstituted in BRCA1 mutated HCC1937 breast cancer cells. We aim (i) to investigate the expression of the whole family of IAPs across a wide range breast cancer cell lines and tumour samples at both the RNA and protein level, and (ii) to determine whether targeting IAPs alters susceptibility to apoptosis. This study tested the hypothesis that Brk is involved in regulating the tumour cell environment during progression and investigated the effects of suppressing Brk in breast carcinoma cells to determine in which contexts Brk may be a valid therapeutic target. Molecular and clinical evidence points to a role for TGFβ signalling in cancer progression and metastasis; it is unclear at which points of the metastatic process TGFβ signalling occurs and whether it is necessary and/or sufficient to elicit cancer cell motility
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