Abstract
BackgroundAneuploidy and chromosomal instability (CIN) are common abnormalities in human cancer. Alterations of the mitotic spindle checkpoint are likely to contribute to these phenotypes, but little is known about somatic alterations of mitotic spindle checkpoint genes in breast cancer.MethodsTo obtain further insight into the molecular mechanisms underlying aneuploidy in breast cancer, we used real-time quantitative RT-PCR to quantify the mRNA expression of 76 selected mitotic spindle checkpoint genes in a large panel of breast tumor samples.ResultsThe expression of 49 (64.5%) of the 76 genes was significantly dysregulated in breast tumors compared to normal breast tissues: 40 genes were upregulated and 9 were downregulated. Most of these changes in gene expression during malignant transformation were observed in epithelial cells.Alterations of nine of these genes, and particularly NDC80, were also detected in benign breast tumors, indicating that they may be involved in pre-neoplastic processes.We also identified a two-gene expression signature (PLK1 + AURKA) which discriminated between DNA aneuploid and DNA diploid breast tumor samples. Interestingly, some DNA tetraploid tumor samples failed to cluster with DNA aneuploid breast tumors.ConclusionThis study confirms the importance of previously characterized genes and identifies novel candidate genes that could be activated for aneuploidy to occur. Further functional analyses are required to clearly confirm the role of these new identified genes in the molecular mechanisms involved in breast cancer aneuploidy. The novel genes identified here, and/or the two-gene expression signature, might serve as diagnostic or prognostic markers and form the basis for novel therapeutic strategies.
Highlights
A very large proportion of cancers consist of cells with an abnormal chromosome content, a feature known as aneuploidy [1]
As aneuploidy is common in breast cancer and is associated with a poor prognosis [9], we examined the expression of selected mitotic spindle checkpoint genes in breast tumors
We identified nine genes involved in early breast tumorigenesis, and a two-gene expression signature (PLK1 + AURKA) associated with aneuploid status
Summary
A very large proportion of cancers consist of cells with an abnormal chromosome content, a feature known as aneuploidy [1]. The normal function of the spindle checkpoint is to ensure that all chromosomes are correctly aligned in metaphase cells and properly attached to the mitotic spindle before chromosome separation can proceed. Like other phenotypes characteristic of cancer, it was first thought that nucleotide mutations in genes that control chromosome stability were responsible for CIN. Despite the importance of the mitotic spindle checkpoint in CIN, no detailed analyses of mitotic spindle checkpoint gene expression in tumors has yet been performed. Alterations of the mitotic spindle checkpoint are likely to contribute to these phenotypes, but little is known about somatic alterations of mitotic spindle checkpoint genes in breast cancer
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