Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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LCN2 Promoter Methylation Status as Novel Predictive Marker for Microvessel Density and Aggressive Tumor Phenotype in Breast Cancer Patients

  • Published : 2015.07.13
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Abstract

LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients.

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References

  1. Bartsch S, Tschesche H (1995).Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. FEBS Lett, 357, 255-9. https://doi.org/10.1016/0014-5793(94)01303-I
  2. Bauer M, Eickhoff JC, Gould MN, et al. (2008). Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat, 108, 389-97. https://doi.org/10.1007/s10549-007-9619-3
  3. De, Loriot A, Boon T (2004). Promoter-dependent mechanism leading to selective hypomethylation within the 50region of gene MAGE-A1 in tumor cells. Mol Cell Biol, 24, 4781-4790. https://doi.org/10.1128/MCB.24.11.4781-4790.2004
  4. Fernandez CA, Yan L, Louis, G, et al (2005). The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res, 11, 5390-5. https://doi.org/10.1158/1078-0432.CCR-04-2391
  5. Gerald W, Prager Marina P, Matthias U, et al (2012). Angiogenesis in cancer: anti-VEGF escape mechanisms. Transl Lung Cancer Res, 1, 1.
  6. Hafez MM, Al-Shabanah OA, Al-Rejaie SS, et al (2015). Increased hypermethylation of glutathione s-transferase p1, DNA-binding protein inhibitor, death associated protein kinase and paired box protein-5 genes in triple-negative breast cancer saudi females. Asian Pac J Cancer Prev, 16, 541-9. https://doi.org/10.7314/APJCP.2015.16.2.541
  7. Han LL, Hou L, Zhou MJ, et al (2013). Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer. J Biomed Sci, 20, 52. https://doi.org/10.1186/1423-0127-20-52
  8. Harper J, Moses MA (2006). Molecular regulation of tumor angiogenesis: mechanisms and therapeutic implications. EXS, 96, 223-68.
  9. Jovanovic J, Ronneberg JA, Tost J, et al (2010). The epigenetics of breast cancer. Mol Oncol, 4, 242-54. https://doi.org/10.1016/j.molonc.2010.04.002
  10. Klintman M, Bendahl PO, Grabau D, et al (2010). The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer. Mod Pathol, 23, 251-9. https://doi.org/10.1038/modpathol.2009.167
  11. Lee HJ, Lee EK, Lee KJ, et al (2006). Ectopic expression of neutrophil gelatinase-associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells. Int J Cancer, 118, 2490-7. https://doi.org/10.1002/ijc.21657
  12. Lim R, Ahmed N, Borregaard N. (2007). Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition. Int J Cancer, 120, 2426-34. https://doi.org/10.1002/ijc.22352
  13. Nielsen BS, Borregaard N, Bundgaard JR, et al. (1996). Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut, 38, 414-20. https://doi.org/10.1136/gut.38.3.414
  14. Pikor LA1, Enfield KS, Cameron H, et al (2011). DNA Extraction from Paraffin Embedded Material for Genetic and Epigenetic Analyses. J Vis Exp, 49, 2763.
  15. Pitashny M, Schwartz N, Qing X, et al (2007). Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum, 56, 1894-903. https://doi.org/10.1002/art.22594
  16. Place TL, Fitzgerald MP, Venkataraman S, et al (2013). Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. PLoS ONE, 6, 14617.
  17. Roll JD, Rivenbark AG, Jones WD, et al (2008). DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer, 7, 15 https://doi.org/10.1186/1476-4598-7-15
  18. Stoesz SP, Friedl A, Haag JD, et al (1998). Heterogeneous expression of the Lipocalin NGAL in primary breast cancers. Int J Cancer, 79, 565-72. https://doi.org/10.1002/(SICI)1097-0215(19981218)79:6<565::AID-IJC3>3.0.CO;2-F
  19. Tae K, El-Naggar AK, et al (2000). Expression of vascular endothelial growth factor and microvessel density in head and neck tumorigenesis. Clin Cancer Res, 6, 2821-8.
  20. Taweevisit M, Keelawat S, Scott Thorner P. (2010). Correlation of microvascular density and proliferation index in undifferentiated nasopharyngeal carcinoma. Asian Biomedicine, 4, 315-21.
  21. Viau A, El Karoui K, Laouari D, et al (2010). Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest, 120, 4065-76. https://doi.org/10.1172/JCI42004
  22. Yang J, McNeish B, Butterfield C, Moses MA. (2013). Lipocalin 2 is a novel regulator of angiogenesis inhuman breast cancer. FASEB J, 1, 45-50.
  23. Yang J, Moses MA (2009). Lipocalin 2: A Multifaceted Modulator of Human Cancer. Cell Cycle, 15, 2347-52.
  24. Yuan J, Luo RZ, Fujii S, et al (2003). Aberrant Methylation and Silencing of ARHI an imprinted tumor suppressor gene in which the function is lost in breast cancer. Cancer Res, 63, 4174-80.

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