Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth

Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. What's new? Induced overexpression of the receptor tyrosine kinase c-kit in metastatic bone lesions in prostate cancer suggests that interactions between cancer cells and the bone microenvironment play a key role in progression of the disease. The nature of those interactions, however, is not fully understood. This study shows that activation of c-kit in prostate cancer cells results in BRCA2 downregulation, while re-expression of BRCA2 reduces c-kit protein expression. Loss of BRCA2 is known to promote migration and invasion in prostate cancer cells. Thus, the findings suggest that c-kit activation is an important contributor to bone metastasis in prostate cancer.