Growth-related oncogene produced in human breast cancer cells and regulated by Syk protein-tyrosine kinase

Abstract

Syk, a nonreceptor type of protein tyrosine kinase widely expressed in hematopoietic cells, is a candidate suppressor gene in human breast cancer. Reduced expression of Syk protein is correlated with poor prognosis, while its overexpression can reduce the malignant phenotype of breast cancer cells. The mechanism of action of Syk remains unclear. In this study, we utilized low Syk-expressing, highly invasive MDA-MB-231 and high Syk-expressing, less invasive MCF-7 breast cancer cells to investigate the possibility that part of the functional effects of Syk are mediated by cytokines known to play roles in cell migration, invasion or metastasis. Using protein array technology, we determined that MDA-MB-231 cells secrete a number of cytokines known to regulate cellular growth and motility. One such cytokine, growth-related oncogene (GRO), has previously not been described in breast cancer. Of the compounds detected in the culture supernatant of MDA-MB-231, GRO was the only one that was significantly altered by modulation of Syk expression; overexpression of Syk caused a marked reduction in secreted levels of GRO. Conversely, downregulation of the relatively high levels of Syk produced in MCF-7 cells upregulated GRO secretion. At the mRNA level, overexpression of Syk in MDA-MB-231 differentially regulated the 3 GRO isotypes such that message levels of GROalpha and gamma were downregulated while that of GRObeta was not affected. Matrigel invasion assays demonstrated a link between Syk expression and resulting GRO activity in mediating the invasive potential of MDA-MB-231 cells. In summary, our findings provide evidence that human breast cancer cells express and secrete GRO and implicate this cytokine as an essential mediator of the antiinvasive properties of Syk tyrosine kinase.