Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-Regulation of Hexokinase 2 and Poor Prognosis

Abstract

Brain metastases of breast cancer seem to be increasing in 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, LAMγ3, 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 glucoselimiting 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. (Mol Cancer Res 2009;7(9):1438-45)

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…29 Although in normal brain and low-grade gliomas HK-I is the predominant isoform, HK-II is highly upregulated in human glioblastoma multiforme 30 and poor prognosis is associated with upregulation of HK-II in human brain metastases of breast cancer. 31 Thus HK-II upregulation is considered a consequence of metabolic re-programming in cancer.…”

Tumor‐suppressive microRNA‐143/145 cluster targets hexokinase‐2 in renal cell carcinoma

“…(36) In a clinical study, over-expression of HK2 was associated with brain metastasis of breast cancer. (37) The detailed molecular mechanisms that overexpression of HK2 causes in cancer cell invasion and metastasis are still unclear and it is a future research theme. Interestingly, we also found that GLUT1 was overexpressed in RCC cells and that GLUT1 was directly regulated by tumor-suppressive miR-1291.…”

Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma

“…Two homologues, Siah1 and Siah2, have been shown to be involved in the response to DNA damage, the hypoxic response, inflammation, and several oncogenic signals including those propagated by Ras and epidermal growth factor receptor (EGFR) [10][11][12][13]. To date, few studies have addressed the role of Siah expression in cancer, and there has been no consensus as to the biologic significance of such expression [14,15]. Thus, Siah expression and its role in the molecular pathogenesis of cancer, including NPC, remain unknown.…”