Expression of variant forms of the MUC1 gene correlates with the invasiveness of breast cancer cells

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The characterization of tumor markers is of prime importance in understanding the mechanisms underlying cancer initiation and progression. The most exclusively used marker for monitoring breast cancer patients are the protein products of the MUC1 gene, which is strongly overexpressed in breast cancer cells. The best characterized MUC1 gene product is MUC1/REP (episialin, PEM, CA15-3, MCA). It is important in reducing cell-cell and cell-extracellular matrix interactions, probably being involved in the spread of cancer cells from the primary tumor. MUC1 overexpression was found to correlate with invasiveness. Four isoforms are generated by differential splicing due to the use of alternative splice acceptor sites for exon 1. These were designated variants A to D. A higher expression of variant A than of variant B was found to indicate thyroid papillary carcinomas.

We investigated the expression of these variant forms in 23 permanent breast cell lines. RNA samples were analyzed by RT-PCR and subsequent automated quantitative fragment analysis. The cell lines were also analyzed for invasiveness by an in vitro collagen invasion assay. Ten cell lines showed invasive growth, either as single cells or as cell clusters. Variant A was solely expressed in four of the invasive cell lines and was preferentially expressed in one line (ratio 35.1), whereas only 1 out of 13 non-invasive cell lines expressed more variant A than variant B (ratio 1.1). This correlation between the mRNA expression of variant A and the in vitro invasiveness was statistically significant (P = 0.035). Moreover, variant D was concomitantly found with the preferentially expressed variant A.

This is the first report about the correlation of expression of a MUC1 splice variant and the invasiveness of breast cancer cells. We conclude that not only overexpression of MUC1 in cancer cells is responsible for metastasis, but also the expression of variant forms.