MCPH1, a potential predictor for response to cancer chemotherapy
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KeywordsBreast Cancer Taxol Microcephaly Nocodazole Spindle Assembly Checkpoint
We previously identified MCPH1, a DNA damage response protein involved in the regulation of the breast cancer tumour suppressor gene BRCA1, as the defective protein in one form of microcephaly . We found that reduced expression of MCPH1 causes premature chromosome condensation (PCC) . PCC is a hallmark of mammalian cells that begin mitosis before completing DNA replication. The MCPH1 locus (8p22-p23) is frequently deleted in many tumour types and this is associated with a poor prognosis and a reduced response to chemotherapy in breast cancer . Many chemotherapeutic agents such as taxanes (for example, Taxol) require a functional spindle checkpoint for the induction of apoptosis in cancer cells.
Using time-lapse imaging we have studied mitotic progression in MCPH1-deficient cells. The presence of a functional spindle assembly checkpoint was tested for using two different spindle poisons – for example, Taxol and nocodazole – in MCPH1-deficient cells. Immunohistochemistry using a MCPH1 antibody was performed on 54 breast cancer samples and was correlated with pathology data.
We have identified a number of mitotic defects including slower mitotic progression displaying aberrant chromosomal congression and micronuclei formation in MCPH1-deficient cells. MCPH1-deficient cells displayed a reduced mitotic arrest in response to spindle poisons, indicating impairment of the spindle checkpoint. Our immunohistochemistry data have identified reduced MCPH1 expression in 32% (17/54) of breast cancers, particularly in higher grade tumours.
The mitotic phenotype suggests that loss of MCPH1 function in tumours could cause mitotic errors resulting in aneuploidy development. Our data indicate MCPH1 plays a role in resistance to chemotherapeutic agents such as Taxol through its involvement in the spindle checkpoint and apoptosis. We therefore hypothesise that, while germline defects in MCPH1 cause microcephaly, somatic defects may cause aneuploidy development and resistance to chemotherapy in breast cancer.
Supported by Yorkshire Cancer Research.
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