Abstract
C-terminal binding proteins (CtBPs) (CtBP1 and CtBP2) are dual-function proteins that act in the nucleus as transcriptional co-repressors and in the cytoplasm as regulators of mitotic Golgi fissioning. They have been implicated in the process of cellular transformation through their physical and functional interactions with the viral oncoproteins adenovirus E1A, and EBNA3C. Studies in which the expression or function of CtBPs has been suppressed in mammalian cells have independently identified both a role in suppressing apoptosis, through their regulation of transcription of proapoptotic genes, and a requirement for cell-cycle progression, dependent on their role in the Golgi. Here we have undertaken a holistic analysis of the phenotypic consequences of ablating CtBP expression in breast cancer-derived cell lines. We find that loss of CtBPs suppresses the proliferation of these lines through a combination of induction of apoptosis, reduction in cell-cycle progression into mitosis, and aberrations in transit through mitosis itself. This third phenotype includes errors in mitotic chromosome segregation, activation of, but failure to sustain, the spindle assembly checkpoint, diminished localisation of spindle checkpoint proteins at kinetochores, and a high rate of failure to complete cytokinesis. These represent novel roles for CtBPs in the regulation of critical stages of the cell division cycle.
Highlights
Obesity will soon be the leading preventable risk factor for many cancers
Previous epidemiological studies have investigated the relationship between individual nutrients such as vitamin D and O3 vitamin B12 and mammographic density, a strong marker of breast cancer risk [1], with varied results
We have demonstrated that this paradigm applies to mammary epithelial cells, which undergo a switch from Th1 to Th2 cytokine production upon the induction of differentiation
Summary
Obesity will soon be the leading preventable risk factor for many cancers. The insulin-like growth factors (IGFs) have been strongly implicated as important risk factors for many epithelial cancers, including breast cancer, and for mediating the link between nutrition and these cancers. Overexpression of 15-PGDH partially restored sensitivity of TAMr cells to 4-hydroxytamoxifen by the MTT assay, demonstrating that 15-PGDH downregulation plays a functional role in the acquisition of TAMr. Treatment of TAMr MCF-7 cells with a DNA methyltransferase inhibitor (5-azacytidine), and a histone deacetylase inhibitor (trichostatin A), led to re-expression of 15-PGDH mRNA (by quantitative RT-PCR), suggesting that 15-PGDH is silenced via epigenetic mechanisms during the acquisition of TAMr. To address whether 15-PGDH downregulation is involved in clinical TAMr, we assembled a tissue microarray comprising 89 relapsed primary human breast cancers and 234 tamoxifen-sensitive controls. Oestrogen receptor-positive breast cancers develop resistance to anti-oestrogens by utilising alternative growth factor pathways as observed in our tamoxifen-resistant cell line (TAMR) These include EGFR, IGF1-R and Src signalling as well as increased growth and invasion. The tumour size was followed by regular measurement with calipers
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