Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases[J]

Department of Neurosurgery, University of Schleswig-Holstein Medical Center, Campus Kiel, Schittenhelmstrasse 10, 24105 Kiel, Germany.
Journal of Cancer Research and Clinical Oncology (Impact Factor: 3.08). 04/2005; 131(3):191-8. DOI: 10.1007/s00432-004-0629-9
Source: PubMed


Brain metastases are an increasingly common complication in breast cancer patients. The Metastasis Suppressor Genes (MSG) Nm23, KISS1, KAI1, BRMS1, and Mkk4 have been associated with the metastatic potential of breast cancer in vitro and in vivo.
The mRNA expression of Nm23, KISS1, KAI1, BRMS1, and Mkk4 in fresh frozen tissue samples of brain metastases from ductal invasive breast cancer specimens was examined in relation to primary tumors. In a first step, mRNA expression screening was carried out using a semi-quantitative RT-PCR approach, in a second step quantitative real-time RT-PCR was performed on selected specimens. By immunohistochemical staining, gene products were visualized on the protein level.
Semi-quantitative RT-PCR revealed reduced mRNA expression of Nm23, KISS1, KAI1, BRMS, and Mkk4 in brain metastases. Results for KISS1, KAI1, BRMS, and Mkk4 were confirmed by real-time RT-PCR. In detail, mRNA expression reduction in breast cancer brain metastases was tenfold. Expression of MSG could be confirmed by immunohistochemical staining on protein level.
Our investigations revealed significantly reduced mRNA expression of metastases suppressor genes KISS1, KAI1, BRMS1, and Mkk4 in breast cancer brain metastasis. Particularly, in the case of KISS1 and Mkk4, an important role for future treatment of patients with breast cancer brain metastatic lesions can be assumed.

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    • "the decreased expression level of KP - 54 was reported to be associated with more aggressive ovarian cancer progression and worse patient prognosis . This study provides validity that KiSS - 1 / GPR54 can reduce cancer cell invasion . Similarly , a study reported that mRNA expression of KiSS - 1 gene inhibited brain metastases from breast cancer ( Stark et al . , 2005 ) . It was reported that decreased expression of KiSS - 1 gene results in increased metastatic potential and aggressive tumor progression during gastric cancer ( Dhar et al . , 2004 ) . Yu , ( 2007 ) have studied the protein expression of non - metastatic genes of KiSS - 1 , KAI - 1 , nm23 and p53 in gastric tumors with and without lymp"
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    ABSTRACT: Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers.
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    • "NDRG2 was first cloned from glioblastoma using polymerase chain reaction-based subtractive hybridization by our laboratory in 1999 [14]. Decreased expression of NDRG2 is found in a number of human cancers, including breast cancer [15], clear cell renal cell carcinoma [16], liver cancer and pancreatic cancer [17]. The ectopic expression of NDRG2 suppresses the proliferation of tumor cells [14], [18], [19]. "
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    ABSTRACT: Hyperthermia (HT) has been proven to be able to alter the invasion capacity of cancer cells. However, the detailed mechanisms responsible for the anti-metastasis effects of HT have not been elucidated. N-myc downstream-regulated gene 2 (NDRG2), as a member of the NDRG family, has been suggested to be highly responsive to various stresses and is associated with tumor suppression. The present study aimed to investigate the biological role of NDRG2 in the invasion of human hepatocellular carcinoma (HCC) cells exposed to HT. We found that NDRG2 could be induced by HT at 45°C. In addition, NDRG2 overexpression inhibited the expression of matrix metallo proteinases-2 (MMP-2) and MMP-9 as well as the invasion of HCC cells, whereas knockingdown NDRG2 reversed the anti-invasion effect of HT in vivo. Further investigation revealed that the phosphorylation level of ERK1/2, but not that of JNK and p38MAPK, was reduced in NDRG2 overexpressing cells. Moreover, the knockdown of NDRG2 expression resulted in increased cell invasion, which was rescued by treating the HepG2 cells with the ERK1/2 inhibitor PD98059, but not with the p38MAPK inhibitor SB203580 or the JNK inhibitor SP600125. Finally, the synergistic cooperation of HT at 43°C and NDRG2 expression effectively reduced cytotoxicity and promoted the anti-invasion effect of HT at 45°C. Taken together, these data suggest that NDRG2 can be induced by HT and that it mediates the HT-caused inhibition of invasion in HCC cells by suppressing the ERK1/2 signaling pathway. The combined application of constitutive NDRG2 expression with HT may yield an optimized therapeutic benefit.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "Over-expression of NM23-H1 in metastatic cell lines reduced cell motility in vitro assays and metastatic potential in xenograft models [29]. Melanoma and breast cancer with a low expression of NM23 appeared to be more at risk of developing brain metastases [30,31]. Suzuki et al. [30] found that NM23-H1 strongly inhibited the liver metastasis of HT-29 cells in nude mice and inhibited the epidermal growth factor-induced cell migration in vitro. "
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