Geminin regulates DNA replication and predicts clinical outcome in breast cancer


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Mike Gonzalez

MRC Cancer Cell Unit, Cambridge, UK

Abstract

Geminin regulates DNA replication and predicts clinical outcome in breast cancer

In order to maintain genomic stability, DNA replication is limited to once per cell cycle by multiple conserved mechanisms. An essential level of control involves a small protein called geminin. Loss of geminin causes asynchronous over-replication of DNA in both primary and transformed mammalian cells. Interestingly, we found that geminin is continuously degraded in mouse trophoblast giant cells that undergo endoreduplication to acquire a >1000C DNA content. We further show that genetic ablation of geminin in the mouse results in an early developmental arrest at the eight-cell stage. All cells in geminin-deficient mouse embryos lack pluripotent stem cells and consist exclusively of trophoblast giant cells.

Downregulation of geminin might possibly be expected to partly account for the high DNA content observed in cancer cells. However, invasive breast carcinomas and cell lines were scanned for mutation or deletion of the geminin gene but no abrogations were found, arguing against a tumour suppressor role for this negative regulator of DNA replication. Instead, we found that geminin maintains its phase-specific expression and is present from S phase to mitosis in breast carcinoma tissue and cell lines, disappearing abruptly at the metaphase:anaphase transition. In women with early breast cancer, both poor overall survival and the development of distant metastases were predicted by a high frequency of geminin expression. Hence, while proteins such as MCMs identify all non-quiescent cycling cells, geminin represents a novel cell cycle biomarker that specifically identifies the sub-fraction of cells that have entered S phase but not exited mitosis.