Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Effect of NUCKS-1 Overexpression on Cytokine Profiling in Obese Women with Breast Cancer

  • Published : 2014.01.30
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Abstract

Background: Overweight and obesity are recognized as major drivers of cancers including breast cancer. Several cytokines, including interleukin-6 (IL-6), IL-10 and lipocalin 2 (LCN2), as well as dysregulated cell cycle proteins are implicated in breast carcinogenesis. The nuclear, casein kinase and cyclin-dependent kinase substrate-1 (NUCKS-1), is a nuclear DNA-binding protein that has been implicated in several human cancers, including breast cancer. Objectives: The present study was conducted to evaluate NUCKS-1 mRNA expression in breast tissue from obese patients with and without breast cancer and lean controls. NUCKS-1 expression was correlated to cytokine profiles as prognostic and monitoring tools for breast cancer, providing a molecular basis for a causal link between obesity and risk. Materials and Methods: This study included 39 females with breast cancer (G III) that was furtherly subdivided into two subgroups according to cancer grading (G IIIa and G IIIb) and 10 control obese females (G II) in addition to 10 age-matched healthy lean controls (G I). NUCKS-1 expression was studied in breast tissue biopsies by means of real-time PCR (RT-PCR). Serum cytokine profiles were determined by immunoassay. Lipid profiles and glycemic status as well as anthropometric measures were also recorded for all participants. Results: IL-6, IL-12 and LCN2 were significantly higher in control obese and breast cancer group than their relevant lean controls (p<0.05), while NUCKS-1 mRNA expression was significantly higher in the breast cancer group compared to the other groups (p<0.05). Significant higher levels of IL-6, IL-12, and LCN2 as well as NUCKS-1 mRNA levels were reported in G IIIb than G IIIa, and positively correlated with obesity markers in all obese patients. Conclusions: Evaluation of cytokine levels as well as related gene expression may provide a new tool for understanding interactions for three axes of carcinogenesis, innate immunity, inflammation and cell cycling, and hope for new strategies of management.

Keywords

References

  1. Abdelsalam KE, Hassan IK, Sadig IA (2012). The role of developing breast cancer in alteration of serum lipid profile. J Res Med Sci, 17, 562-5.
  2. Auguet T, Quintero Y, Terra X, et al (2011). . Obesity, 19, 2295-300Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines. https://doi.org/10.1038/oby.2011.61
  3. Barton BE, Murphy TF (2001). Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. Cytokine, 16, 251-7. https://doi.org/10.1006/cyto.2001.0968
  4. 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
  5. Cejas P, Casado E, Belda-Iniesta C, et al (2004). Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes Control, 15, 707-19. https://doi.org/10.1023/B:CACO.0000036189.61607.52
  6. Cramer EP, Glenthoj A, Hager M, et al (2012). No effect of NGAL/lipocalin-2 on aggressiveness of cancer in the MMTV-PyMT/FVB/N mouse model for breast cancer. PLoS One, 7, 39646-59. https://doi.org/10.1371/journal.pone.0039646
  7. Dandona P, Aljada A, Bandyopadhyay A, et al (2004). Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol, 25, 4-7. https://doi.org/10.1016/j.it.2003.10.013
  8. Derin D, Soydinc HO, Guney N, et al (2007). Serum IL-8 and IL-12 levels in breast cancer. Med Oncol, 24, 163-8. https://doi.org/10.1007/BF02698035
  9. Drosos Y, Kouloukoussa M, Ostvold AC, et al (2009). NUCKS overexpression in breast cancer. Cancer Cell Int, 9, 19-33 https://doi.org/10.1186/1475-2867-9-19
  10. Duseja A, Thumburu KK, Das A, et al (2007). Insulin tolerance test is comparable to homeostasis model assessment for insulin resistance in patients with nonalcoholic fatty liver disease. Indian J Gastroenterol, 26, 170-3.
  11. El-Kadre LJ, Tinoco AC (2013). Interleukin-6 and obesity: the crosstalk between intestine, pancreas and liver. Curr Opin Clin Nutr Metab Care, 16, 564-8.
  12. Fernandez SV, Robertson FM, Pei J, et al (2013). Inflammatory breast cancer (IBC): clues for targeted therapies. Breast Cancer Res Treat, 140, 23-33. https://doi.org/10.1007/s10549-013-2600-4
  13. Friedewald WT, Levy RI, Fredrickson DS (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 18, 499-502.
  14. Gaudet MM, Patel AV, Teras LR, et al (2013). Obesity-related markers and breast cancer in CPS-II Nutrition Cohort. Int J Mol Epidemiol Genet, 4, 156-66.
  15. Giri D, Ozen M, Ittmann M (2001). Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol, 159, 2159-65. https://doi.org/10.1016/S0002-9440(10)63067-2
  16. Gonullu G, Ersoy C, Ersoy A, et al (2005). Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early stage breast cancer. Cytokine, 31, 264-9. https://doi.org/10.1016/j.cyto.2005.05.003
  17. Goodwin PJ, Ennis M, Pritchard KI, et al (2002). Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol, 20, 42-51. https://doi.org/10.1200/JCO.20.1.42
  18. Gorgoulis VG, Vassiliou LV, Karakaidos P, et al (2005). Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature, 434, 907-13. https://doi.org/10.1038/nature03485
  19. Goyal R, Faizy AF, Siddiqui SS, Singhai M (2012). Evaluation of TNF-$\alpha$ and IL-6 levels in obese and non-obese diabetics: Pre- and postinsulin effects. N Am J Med Sci, 4, 180-4. https://doi.org/10.4103/1947-2714.94944
  20. Grundt K, Haga IV, Aleporou-Marinou V, et al (2004). Characterisation of the NUCKS gene on human chromosome 1q32.1 and the presence of a homologous gene in different species. Biochem Biophys Res Commun, 323, 796-801. https://doi.org/10.1016/j.bbrc.2004.08.153
  21. Haura EB, Turkson J, Jove R (2005). Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol, 2, 315-24. https://doi.org/10.1038/ncponc0195
  22. Hsu IR, Kim SP, Kabir M, et al (2007). Metabolic syndrome, hyperinsulinemia, and cancer. Am J Clin Nutr, 86, 867-71
  23. Huffman DM, Barzilai N (2009). Role of visceral adipose tissue in aging. Biochim Biophys Acta, 1790, 1117-23. https://doi.org/10.1016/j.bbagen.2009.01.008
  24. Hussein MZ, Al Fikky A, Abdel Bar I, et al (2004). Serum IL-6 and IL-12 levels in breast cancer patients. Egypt J Immunol, 11, 165-70.
  25. Jones C, Mackay A, Grigoriadis A, et al (2004). Expression profiling of purified normal human luminal and myoepithelial breast cells: Identification of novel prognostic markers for breast cancer. Cancer Res, 64, 3037-45. https://doi.org/10.1158/0008-5472.CAN-03-2028
  26. Kedzierska M, Olas B, Wachowicz B, et al (2010). The lipid peroxidation in breast cancer patients. Gen Physiol Biophys, 29, 208-10.
  27. Law IK, Xu A, Lam KS, et al (2010). Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes, 59, 872-82. https://doi.org/10.2337/db09-1541
  28. Ligibel J (2011). Obesity and breast cancer. Oncology (Williston Park), 25, 994-1000.
  29. Liu R, Wang X, Chen GY, et al (2007). The Prognostic Role of a Gene Signature from Tumorigenic Breast-Cancer Cells. N Engl J Med, 356, 217-26. https://doi.org/10.1056/NEJMoa063994
  30. Liu X, Hamnvik OP, Petrou M, et al (2011). Circulating lipocalin 2 is associated with body fat distribution at baseline but is not an independent predictor of insulin resistance: the prospective Cyprus Metabolism Study. Eur J Endocrinol, 165, 805-12. https://doi.org/10.1530/EJE-11-0660
  31. Matsuoka S, Ballif BA, Smogorzewska A, et al (2007). ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science, 316, 1138-9. https://doi.org/10.1126/science.1143700
  32. Minamino T, Yoshida T, Tateno K, et al (2003). Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation, 108, 2264-9. https://doi.org/10.1161/01.CIR.0000093274.82929.22
  33. Moschos SJ, Mantzoros CS (2002). The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology, 63, 317-32. https://doi.org/10.1159/000066230
  34. Naylor TL, Greshock J, Wang Y, et al (2005). High resolution genomic analysis of sporadic breast cancer using arraybased comparative genomic hybridization. Breast Cancer Res, 7, 1186-98. https://doi.org/10.1186/bcr1356
  35. Nguyen DX, Massague J (2007). Genetic determinants of cancer metastasis. Nat Rev Genet, 8, 341-52.
  36. Nyante SJ, Devries S, Chen YY, et al (2004). Array-based comparative genomic hybridization of ductal carcinoma in situ and synchronous invasive lobular cancer. Hum Pathol, 35, 759-63. https://doi.org/10.1016/j.humpath.2003.11.009
  37. Olsson N, Carlsson P, James P, et al (2013). Grading breast cancer tissues using molecular portraits. Mol Cell Proteomics, 12, 3612-23. https://doi.org/10.1074/mcp.M113.030379
  38. Ostvold AC, Norum JH, Mathiesen S, et al (2001). Molecular cloning of a mammalian nuclear phosphoprotein NUCKS, which serves as a substrate for Cdk1 in vivo. Eur J Biochem, 268, 2430-40. https://doi.org/10.1046/j.1432-1327.2001.02120.x
  39. Parker ED, Folsom AR (2003). Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's Health Study. Int J Obes Relat Metab Disord, 27, 1447-52. https://doi.org/10.1038/sj.ijo.0802437
  40. Parkin DM, Fernandez LM (2006). Use of statistics to assess the global burden of breast cancer. Breast J, 12, 70-80. https://doi.org/10.1111/j.1075-122X.2006.00205.x
  41. Robbins P, Pinder S, de Klerk N, et al (1995). Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol, 26, 873-9. https://doi.org/10.1016/0046-8177(95)90010-1
  42. Roy R, Wewer UM, Zurakowski D, et al (2004). ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem, 279, 51323-30. https://doi.org/10.1074/jbc.M409565200
  43. Salgado R, Benoy I, Weytjens R, et al (2002). Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer. Br J Cancer, 87, 1437-44. https://doi.org/10.1038/sj.bjc.6600655
  44. Sargent LM, Ensell MX, Ostvold AC, et al (2008). Chromosomal changes in high- and low-invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains. Toxicol Appl Pharmacol, 233, 81-91. https://doi.org/10.1016/j.taap.2008.01.031
  45. Sharabiani MT, Vermeulen R, Scoccianti C, et al (2011). Immunologic profile of excessive body weight. Biomarkers, 16, 243-51. https://doi.org/10.3109/1354750X.2010.547948
  46. Silswal N, Singh AK, Aruna B, et al (2005). Human resistin stimulate the pro-inflammatory cytokines TNF-$\alpha$ and IL-12 in macrophages by NF-$\kappa{B}$-dependent pathway. Biochem Biophys Res Commun, 334, 1092-101. https://doi.org/10.1016/j.bbrc.2005.06.202
  47. Smyth MJ, Cretney E, Kershaw MH, et al (2004). Cytokines in cancer immunity and immunotherapy. Immunol Rev, 202, 275-93. https://doi.org/10.1111/j.0105-2896.2004.00199.x
  48. Strissel KJ, DeFuria J, Shaul ME, et al (2010). T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring), 18, 1918-25. https://doi.org/10.1038/oby.2010.1
  49. Suarez-Alvarez K, Solis-Lozano L, Leon-Cabrera S, et al (2013). Serum IL-12 is increased in Mexican obese subjects and associated with low-grade inflammation and obesity-related parameters. Mediators Inflamm, 2013, 967067.
  50. Surendar J, Mohan V, Rao MM, et al (2011). Increased levels of both Th1 and Th2 cytokines in subjects with metabolic syndrome (CURES-103). Diabetes Technol Ther, 13, 477-82. https://doi.org/10.1089/dia.2010.0178
  51. Trinchieri G (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol, 3, 133-46. https://doi.org/10.1038/nri1001
  52. Wang Y, Lam KS, Kraegen EW, et al (2007). Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem, 53, 34-41.
  53. Wiese C, Dray E, Groesser T, et al (2007). Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement. Mol Cell, 28, 482-90. https://doi.org/10.1016/j.molcel.2007.08.027
  54. Wisniewski JR, Zougman A, Kruger S, et al (2008). Constitutive and dynamic phosphorylation and acetylation sites on NUCKS, a hypermodified nuclear protein, studied by quantitative proteomics. Proteins, 73, 710-8. https://doi.org/10.1002/prot.22104
  55. Wu HP, Kuo SF, Wu SY et al (2010). High interleukin-12 production from stimulated peripheral blood mononuclear cells of type 2 diabetes patients. Cytokine, 51, 298-304. https://doi.org/10.1016/j.cyto.2010.06.014
  56. Xiaohong L, Yun W, Ralph BA (2011). Relationships of lipocalin 2 with breast tumorigenesis and metastasis. J Cell Physiol, 226, 309-14. https://doi.org/10.1002/jcp.22403
  57. Xu J, Chen Y, Olopade OI (2010). MYC and Breast Cancer. Genes Cancer, 1, 629-40. https://doi.org/10.1177/1947601910378691
  58. Yang J, Bielenberg DR, Rodig SJ, et al (2009). Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA, 106, 3913-8. https://doi.org/10.1073/pnas.0810617106
  59. Yang J, McNeish B, Butterfield C, et al (2013). Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J, 27, 45-50. https://doi.org/10.1096/fj.12-211730
  60. Zavala G, Long KZ, Garcia OP, et al (2012). Specific micronutrient concentrations are associated with inflammatory cytokines in a rural population of Mexican women with a high prevalence of obesity. Br J Nutr, 29, 1-9.

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