A novel oncogene with a kinase domain (NOK), a receptor protein tyrosine kinase, has been reported to cause proliferation of normal cells, suggesting its possible use as a diagnostic marker in human cancer. To determine the significance of NOK expression in cancer cells, the effect of NOK inhibition was first examined on cell proliferation in vitro. The degree of expression in 52 clinical breast cancer samples was then correlated with clinical features. The transduction of NOK small inhibitory (si) RNA in T47D breast cancer cells decreased NOK mRNA expression, thereby inhibiting growth. When the mean expression in non-cancerous tissues from the same breast resection specimens +/-2SD was used as a cut-off value, 67.3% of breast cancers were positive for NOK expression - a higher positivity rate than that found for c-erbB2 (28.8%). NOK mRNA expression did not correlate with c-erbB2 expression, indicating the independence of NOK as a diagnostic marker. Furthermore, NOK mRNA was highly expressed even at early clinical stages. NOK mRNA might be an ideal target to support the diagnosis of breast cancer especially in tiny tumors in which the malignancy cannot be confirmed by other means.