Drug Discovery Opinion

Inhibitors of the non-receptor spleen tyrosine kinase (Syk) are being developed to treat a variety of allergic and autoimmune disorders, as well as some types of cancer, but researchers at Georgetown University Medical Center have cautioned that Syk controls the growth of normal breast cells and prevents the development of breast cancer.

Although it is not known what causes loss of Syk function, Syk is negatively correlated with invasion and metastasis of tumour cells and, as breast tumours progress, more and more Syk protein is lost. Since total knock-out of Syk is perinatally lethal, the researchers created mice with only one copy of the gene and found that loss of the single allele led to increased proliferation and invasion of normal breast cells in the mouse mammary gland during puberty, and resulted in development of breast cancer in adulthood.

siRNA or shRNA knockdown of Syk protein in cultures of normal human breast epithelial cells also dramatically increased proliferation and invasion. Syk loss was shown to release inhibition of a number of signalling pathways that are normally repressed in epithelial cells and that promote increased proliferation, motility, and invasiveness. The findings, which were published on October 15^th in the journal PLoS ONE, suggest that Syk plays an important role in controlling growth as breast tissue develops and acts as a tumour suppressor for breast cancer. The finding that only partial loss of Syk function in mice was sufficient to induce mammary carcinomas underscores the potential risk of Syk inhibition in promoting breast cancer. The team hope that identification of the pathways that are negatively regulated by Syk will ultimately provide new targets for the treatment of breast cancer.

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