Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Detection of PIK3CA Gene Mutations with HRM Analysis and Association with IGFBP-5 Expression Levels in Breast Cancer

  • Dirican, Ebubekir (Department of Medical Biology, School of Medicine, Marmara University) ;
  • Kaya, Zehra (Department of Medical Biology, School of Medicine, Marmara University) ;
  • Gullu, Gokce (Department of Medical Biology, School of Medicine, Marmara University) ;
  • Peker, Irem (Department of Medical Biology, School of Medicine, Marmara University) ;
  • Ozmen, Tolga (Department of General Surgery, School of Medicine, Marmara University) ;
  • Gulluoglu, Bahadir M. (Department of General Surgery, School of Medicine, Marmara University) ;
  • Kaya, Handan (Department of Pathology, School of Medicine, Marmara University) ;
  • Ozer, Ayse (Department of Medical Biology, School of Medicine, Marmara University) ;
  • Akkiprik, Mustafa (Department of Medical Biology, School of Medicine, Marmara University)
  • Published : 2014.11.28
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Abstract

Breast cancer is the second most common cancer and second leading cause of cancer deaths in women. Phosphatidylinositol-3-kinase (PI3K)/AKT pathway mutations are associated with cancer and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations have been observed in 25-45% of breast cancer samples. Insulin growth factor binding protein-5 (IGFBP-5) can show different effects on apoptosis, cell motility and survival in breast cancer. We here aimed to determine the association between PIK3CA gene mutations and IGFBP-5 expressions for the first time in breast cancer patients. Frozen tumor samples from 101 Turkish breast cancer patients were analyzed with high resolution melting (HRM) for PIK3CA mutations (exon 9 and exon 20) and 37 HRM positive tumor samples were analyzed by DNA sequencing, mutations being found in 31. PIK3CA exon 9 mutations (Q546R, E542Q, E545K, E542K and E545D) were found in 10 tumor samples, exon 20 mutations (H1047L, H1047R, T1025T and G1049R) in 21, where only 1 tumor sample had two exon 20 mutations (T1025T and H1047R). Moreover, we detected one sample with both exon 9 (E542Q) and exon 20 (H1047R) mutations. 35% of the tumor samples with high IGFBP-5 mRNA expression and 29.4% of the tumor samples with low IGFBP-5 mRNA expression had PIK3CA mutations (p=0.9924). This is the first study of PIK3CA mutation screening results in Turkish breast cancer population using HRM analysis. This approach appears to be a very effective and reliable screening method for the PIK3CA exon 9 and 20 mutation detection. Further analysis with a greater number of samples is needed to clarify association between PIK3CA gene mutations and IGFBP-5 mRNA expression, and also clinical outcome in breast cancer patients.

Keywords

References

  1. Ahn BY, Elwi AN, Lee B, et al (2010). Genetic screen identifies insulin-like growth factor binding protein 5 as a modulator of tamoxifen resistance in breast cancer. Cancer Res, 70, 3013-19. https://doi.org/10.1158/0008-5472.CAN-09-3108
  2. Arsenic R, Lehmann A, Budczies J, et al (2014). Analysis of PIK3CA mutations in breast cancer subtypes. Appl Immunohistochem Mol Morphol, 22, 50-6. https://doi.org/10.1097/PDM.0b013e318297afea
  3. Bos PD, Zhang XH, Nadal C, et al (2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459, 1005-9. https://doi.org/10.1038/nature08021
  4. Bachman KE, Argani P, Samuels Y, et al (2004). The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther, 3, 772-5. https://doi.org/10.4161/cbt.3.8.994
  5. Barbareschi M, Buttitta F, Felicioni L, et al (2007). Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res, 13, 6064-69 https://doi.org/10.1158/1078-0432.CCR-07-0266
  6. Campbell IG, Russell SE, Choong DY, et al (2004). Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res, 64,7678-81. https://doi.org/10.1158/0008-5472.CAN-04-2933
  7. Cantley LC (2002). The phosphoinositide 3-kinase pathway. Science, 296, 1655-7. https://doi.org/10.1126/science.296.5573.1655
  8. Daigeler A, Klein-Hitpass L, Stricker I, et al (2010). Malignant fibrous histiocytoma- pleomorphic sarcoma, NOS gene expression, histology, and clinical course. A pilot study. Langenbecks Arch Surg, 395, 261-75. https://doi.org/10.1007/s00423-009-0465-0
  9. Dang XD, Kelleher CT, Howard-Williams E, et al (2012). Rapid identification of chloroplast haplotypes using High Resolution Melting analysis. Mol Ecol Resour, 12, 894-08. https://doi.org/10.1111/j.1755-0998.2012.03164.x
  10. Frierson HF Jr, Wolber RA, Berean KW, et al (1995). Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol, 103, 195-8.
  11. Georgescu MM (2010). PTEN tumor suppressor network in PI3K-AKT pathway control. Genes Cancer, 1, 1170-7. https://doi.org/10.1177/1947601911407325
  12. Grimberg A, Cohen P (2000). Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol, 183, 1-9. https://doi.org/10.1002/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J
  13. He ML, Wu Y, Zhao JM et al (2013). PIK3CA and AKT gene polymorphisms in susceptibility to osteosarcoma in a Chinese population. Asian Pac J Cancer Prev, 14, 5117-22. https://doi.org/10.7314/APJCP.2013.14.9.5117
  14. Hermani A, Shukla A, Medunjanin S, et al (2013). Insulin-like growth factor binding protein-4 and -5 modulate liganddependent estrogen receptor-alpha activation in breast cancer cells in an IGF-independent manner. Cell Signal, 25, 1395-02. https://doi.org/10.1016/j.cellsig.2013.02.018
  15. Huang G, Dang ZF, Dang YM, et al (2014). Expression and underlying roles of IGFBP-3 in paclitaxel-treated gastric cancer Sgc-7901 cells. Asian Pac J Cancer Prev, 15, 5741-5. https://doi.org/10.7314/APJCP.2014.15.14.5741
  16. Huynh H (1998). In vivo regulation of the insulin-like growth factor system of mitogens by human chorionic gonadotropin. Int J Oncol, 13, 571-75.
  17. Hollestelle A, Elstrodt F, Nagel JH, et al (2007). Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res, 5, 195-01. https://doi.org/10.1158/1541-7786.MCR-06-0263
  18. Jiang YZ, Yu KD, Bao J, et al (2014). Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. Cancer Res, 74, 3399-407. https://doi.org/10.1158/0008-5472.CAN-14-0092
  19. Kandula M, Chennaboina KK, Ys AR, et al (2013). Phosphatidylinositol 3-kinase (PI3KCA) oncogene mutation analysis and gene expression profiling in primary breast cancer patients. Asian Pac J Cancer Prev, 14, 5067-72. https://doi.org/10.7314/APJCP.2013.14.9.5067
  20. Karamouzis MV, Papavassiliou AG (2012). Targeting insulin-like growth factor in breast cancer therapeutics. Crit Rev Oncol Hematol, 84, 8-17. https://doi.org/10.1016/j.critrevonc.2012.02.010
  21. Lai YL, Mau BL, Cheng WH, et al (2008). PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol, 15, 1064-69. https://doi.org/10.1245/s10434-007-9751-7
  22. Lerma E, Catasus L, Gallardo A, et al (2008). Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas. Virchows Arch, 453, 133-9. https://doi.org/10.1007/s00428-008-0643-4
  23. Lee JW, Soung YH, Kim SY, et al (2005). PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcino mas. Oncogene, 24, 1477-80. https://doi.org/10.1038/sj.onc.1208304
  24. Levine DA, Bogomolniy F, Yee CJ, et al (2005). Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res, 11, 2875-78. https://doi.org/10.1158/1078-0432.CCR-04-2142
  25. Li SY, Rong M, Grieu F, et al (2006). PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat, 96, 91-5. https://doi.org/10.1007/s10549-005-9048-0
  26. Ligresti G, Militello L, Steelman LS, et al (2009). PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle, 8, 1352-8. https://doi.org/10.4161/cc.8.9.8255
  27. Liu CX, Li XY, Li CF, et al (2014). Compound HRAS/PIK3CA mutations in Chinese patients with alveolar rhabdomyosarcomas. Asian Pac J Cancer Prev, 15, 1771-4. https://doi.org/10.7314/APJCP.2014.15.4.1771
  28. Maruyama N, Miyoshi Y, Taguchi T, et al (2007). Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res, 13, 408-14 https://doi.org/10.1158/1078-0432.CCR-06-0267
  29. McGuire SE, Hilsenbeck SG, Figueroa JA, et al (1994). Detection of insulin-like growth factor binding proteins (IGFBPs) by ligand blotting in breast cancer tissues. Cancer Lett, 77, 25-32. https://doi.org/10.1016/0304-3835(94)90343-3
  30. Mita K, Zhang Z, Ando Y, et al (2007). Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer. Jpn J Clin Oncol, 37, 575-82. https://doi.org/10.1093/jjco/hym066
  31. Ney JT, Froehner S, Roesler A, et al (2012). High- resolution melting analysis asa sensitive prescreening diagnostic tool to detect KRAS, BRAF, PIK3CA , and AKT1 mutations in formalin-fixed, paraffin-embedded tissues. Arch Pathol Lab Med, 136, 983-92. https://doi.org/10.5858/arpa.2011-0176-OA
  32. Osaki M, Oshimura M, Ito H (2004). PI3K-AKT pathway: its functions and alterations in human cancer. Apoptosis, 9, 667-76. https://doi.org/10.1023/B:APPT.0000045801.15585.dd
  33. Ozmen V, Anderson BO (2008). The challenge of breast cancer in low-and middle-income countries-implementing the breast health global initiative guidelines. US Oncology, 76-79.
  34. Pan F, Hong LQ (2014). Insulin promotes proliferation and migration of breast cancer cells through the extracellular regulated kinase pathway. Asian Pac J Cancer Prev, 15, 6349-52. https://doi.org/10.7314/APJCP.2014.15.15.6349
  35. Parsons DW, Jones S, Zhang X, et al (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321, 1807-12. https://doi.org/10.1126/science.1164382
  36. Pekonen F, Nyman T, Ilvesmak V, et al (1992). Insulin-like growth factor binding proteins in human breast cancer tissue. Cancer Res, 52, 5204-7.
  37. Perez Tenorio G, Alkhori L, Olsson B, et al (2007). PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res, 13, 3577-84 https://doi.org/10.1158/1078-0432.CCR-06-1609
  38. Polanco TA, Crismale-Gann C, Reuhl KR, et al (2010). Fetal alcohol exposure increases mammary tumor susceptibility and alters tumor phenotype in rats. Alcohol Clin Exp Res, 34, 1879-87. https://doi.org/10.1111/j.1530-0277.2010.01276.x
  39. Saal LH, Holm K, Maurer M, et al (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res, 65, 2554-9. https://doi.org/10.1158/0008-5472-CAN-04-3913
  40. Samuels Y, Wang Z, Bardelli A, et al (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304-554
  41. Samuels Y, Velculescu VE (2004). Oncogenic mutations of PIK3CA in human cancers. Cell Cycle, 3,1221-24. https://doi.org/10.4161/cc.3.10.1164
  42. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al (2008). An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res, 68, 6084-91. https://doi.org/10.1158/0008-5472.CAN-07-6854
  43. Studer B, Jensen LB, Fiil A, et al (2009). "Blind" mapping of genic DNA sequence polymorphisms in Lolium perenne L. by high resolution melting curve analysis. Molecular Breeding, 24, 191-9. https://doi.org/10.1007/s11032-009-9291-x
  44. Sui JQ, Xie KP, Zou W, et al (2014). Emodin inhibits breast cancer cell proliferation through the $ER{\alpha}$-MAPK/Akt-cyclin D1/Bcl-2 signaling pathway. Asian Pac J Cancer Prev, 15, 6247-51. https://doi.org/10.7314/APJCP.2014.15.15.6247
  45. Taylor KJ, Sims AH, Liang L, et al (2010). .Dynamic changes in gene expression in vivo predict prognosis of tamoxifen treated patients with breast cancer. Breast Cancer Res, 12, 39.
  46. The Cancer Genome Atlas (TCGA) 2008.
  47. Thomas RK, Baker AC, Debiasi RM, et al (2007). High throughput oncogene mutation profiling in human cancer. Nat Genet, 39, 347-51 https://doi.org/10.1038/ng1975
  48. Tong L, Yang XX, Liu MF, et al (2012). Mutational analysis of key EGFR pathway genes in Chinese breast cancer patients. Asian Pac J Cancer Prev, 13, 5599-603. https://doi.org/10.7314/APJCP.2012.13.11.5599
  49. Widodo I, Dwianingsih EK, Triningsih E, et al (2014). . Clinicopathological features of Indonesian breast cancers with different molecular subtypes. Asian Pac J Cancer Prev, 15, 6109-13. https://doi.org/10.7314/APJCP.2014.15.15.6109
  50. Wood LD, Parsons DW, Jones S, et al (2007). The genomic landscapes of human breast and colorectal cancers. Science, 318, 1108-13. https://doi.org/10.1126/science.1145720
  51. Wu G, Xing M, Mambo E, et al (2005). Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res, 7, 609-16. https://doi.org/10.1186/bcr1262
  52. Vogt PK, Hart JR, Gymnopoulos M, et al (2010). Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol, 347, 79-104.
  53. Valentinis B, Baserga R (2001). IGF-I receptor signalling in transformation and differentiation. Mol Pathol, 54, 133-7. https://doi.org/10.1136/mp.54.3.133
  54. Yamaguchi H, Yoshida S, Muroi E, et al (2011). Phosphoinositide 3-kinase signaling pathway mediated by $p110{\alpha}$ regulates invadopodia formation. J Cell Biol, 193, 1275-88. https://doi.org/10.1083/jcb.201009126
  55. Yamashita H, Takahashi S, Ito Y, et al (2009). Predictors of response to exemestane as primary endocrine therapy in estrogen receptor positive breast cancer. Cancer Sci, 100, 2028-33. https://doi.org/10.1111/j.1349-7006.2009.01274.x

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