Reelin expression in breast tumours is associated with increased survival and is controlled by promoter methylation

Background

Reelin is a secreted signalling protein whose major function has so far been described in the developing brain, where it is involved in cell positioning of neuronal progenitor cells. Recently, the Reelin promoter has been found to be methylated in pancreatic cancer and this was associated with increased migratory ability [1], whereas in the prostate Reelin expression is associated with high-grade cancers [2].

Methods

We measured the Reelin expression and promoter methylation status in breast cancer-derived cell lines and in a cohort of 64 breast cancer cases. We further stained sections of normal, benign, and cancerous human breast, as well as two tissue arrays of 168 and 2,200 breast cancer patients, respectively. Reelin staining was analysed with regards to other clinical parameters and survival.

Results

Promoter methylation status in breast cancer cell lines, as well as in primary cancers, corresponds with reduced expression of Reelin. In the normal breast, Reelin is expressed in the luminal epithelium and myoepithelium, but is lost during breast cancer progression. Reelin expression correlates with increased survival (P = 0.01) and negative lymph node status. Treatment of breast cancer cell lines with the demethylating agent decitabine leads to re-expression of Reelin RNA.

Conclusion

Reelin expression in the breast is associated with increased survival and negative lymph node status, and is controlled at least in part by promoter methylation. Reelin is therefore a novel potential tumour suppressor gene in the breast.