Brain metastases of
breast cancer seem to be increasingin incidence as systemic
therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of
laser-captured epithelial cells from resected human
brain metastases of
breast cancer compared with unlinked primary
breast tumors. The
tumors were matched for histology,
tumor-node-
metastasis stage, and
hormone receptor status. Most differentially expressed genes were down-regulated in the
brain metastases, which included, surprisingly, many genes associated with
metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMgamma3, SIAH, STHMN3, and TSPD2.
Hexokinase 2 (HK2) was also of interest because of its increased expression in
brain metastases. HK2 is important in
glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both
mRNA and
protein) were elevated in a brain metastatic derivative (231-BR) of the human
breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using
short hairpin RNA reduced cell proliferation when cultures were maintained in
glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected
brain metastases of
breast cancer. High HK2 expression was significantly associated with poor patient survival after
craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with
metastasis to the brain in
breast cancer and it may be a therapeutic target.