DOI QR코드

DOI QR Code

AXIN2 Polymorphisms, the β-Catenin Destruction Complex Expression Profile and Breast Cancer Susceptibility

  • Published : 2015.11.04

Abstract

Background: The Wnt/${\beta}$-catenin signaling pathway is an important regulator of cellular functions such as proliferation, survival and cell adhesion. Wnt/${\beta}$-catenin signaling is associated with tumor initiation and progression; ${\beta}$-catenin mutations explain only 30% of aberrant signaling found in breast cancer, indicating that other components and/or regulation of the Wnt/${\beta}$-catenin pathway may be involved. Objective: We evaluated AXIN2 rs2240308 and rs151279728 polymorphisms, and expression profiles of ${\beta}$-catenin destruction complex genes in breast cancer patients. Materials and Methods: We collected peripheral blood samples from 102 breast cancer and 102 healthy subjects. The identification of the genetic variation was performed using PCR-RFLPs and DNA sequencing. RT-qPCR was used to determine expression profiles. Results: We found significant association of AXIN2 rs151279728 and rs2240308 polymorphisms with breast cancer risk. Significant increase was observed in AXIN2 level expression in breast cancer patients. Further analyses showed APC, ${\beta}$-catenin, CK1${\alpha}$, GSK3${\beta}$ and PP2A gene expression to be associated to clinic-pathological characteristics. Conclusions: The present study demonstrated, for the first time, that AXIN2 genetic defects and disturbance of ${\beta}$-catenin destruction complex expression may be found in breast cancer patients, providing additional support for roles of Wnt/${\beta}$-catenin pathway dysfunction in breast cancer tumorigenesis. However, the functional consequences of the genetic alterations remain to be determined.

Keywords

References

  1. Alanazi MS, Parine NR, Shaik JP, et al (2013). Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients. PLoS One, 8, 59555. https://doi.org/10.1371/journal.pone.0059555
  2. Brito C, Portela MC, Vasconcellos MT (2009). Survival of breast cancer women in the state of Rio de Janeiro, Southeastern Brazil. Rev Saude Publica, 43, 481-9. https://doi.org/10.1590/S0034-89102009000300012
  3. Castiglia D, Bernardini S, Alvino E, et al (2008). Concomitant activation of Wnt pathway and loss of mismatch repair function in human melanoma. Genes Chromosomes Cancer, 47, 614-24. https://doi.org/10.1002/gcc.20567
  4. Clevers H, Nusse R (2012). Wnt/beta-catenin signaling and disease. Cell, 149, 1192-205. https://doi.org/10.1016/j.cell.2012.05.012
  5. Chapman A, Durand J, Ouadi L, et al (2011). Identification of genetic alterations of AXIN2 gene in adrenocortical tumors. J Clin Endocrinol Metab, 96, 1477-81. https://doi.org/10.1210/jc.2010-2987
  6. Dong X, Seelan RS, Qian C, et al (2001). Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet Cell Genet, 93, 26-8. https://doi.org/10.1159/000056942
  7. Gabrovska PN, Smith RA, Tiang T, et al (2012). Development of an eight gene expression profile implicating human breast tumours of all grade. Mol Biol Rep, 39, 3879-92. https://doi.org/10.1007/s11033-011-1167-6
  8. Gunes EG, Pinarbasi E, Pinarbasi H, et al (2009). Strong association between lung cancer and the AXIN2 polymorphism. Mol Med Report, 2, 1029-35.
  9. Han Y, Zhou L, Ma L, et al (2014). The axis inhibition protein 2 polymorphisms and non-syndromic orofacial clefts susceptibility in a Chinese Han population. J Oral Pathol Med, 43, 554-60. https://doi.org/10.1111/jop.12162
  10. Herbst A, Jurinovic V, Krebs S, et al (2014). Comprehensive analysis of beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling. BMC Genomics, 15, 74. https://doi.org/10.1186/1471-2164-15-74
  11. Howe LR, Brown AM (2004). Wnt signaling and breast cancer. Cancer Biol Ther, 3, 36-41. https://doi.org/10.4161/cbt.3.1.561
  12. Jho EH, Zhang T, Domon C, et al (2002). Wnt/beta-catenin/ Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol, 22, 1172-83. https://doi.org/10.1128/MCB.22.4.1172-1183.2002
  13. Jonsson M, Borg A, Nilbert M, et al (2000). Involvement of adenomatous polyposis coli (APC)/beta-catenin signalling in human breast cancer. Eur J Cancer, 36, 242-8. https://doi.org/10.1016/S0959-8049(99)00276-2
  14. Kanzaki H, Ouchida M, Hanafusa H, et al (2006). Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population. Int J Mol Med, 18, 279-84.
  15. Kao SH, Wang WL, Chen CY, et al (2014). GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug. Oncogene, 33, 3172-82. https://doi.org/10.1038/onc.2013.279
  16. Khalil S, Tan GA, Giri DD, et al (2012). Activation status of Wnt/ ss-catenin signaling in normal and neoplastic breast tissues: relationship to HER2/neu expression in human and mouse. PLoS One, 7, 33421. https://doi.org/10.1371/journal.pone.0033421
  17. Klarmann GJ, Decker A, Farrar WL (2008). Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics, 3, 59-63. https://doi.org/10.4161/epi.3.2.5899
  18. Lamb R, Ablett MP, Spence K, et al (2013). Wnt pathway activity in breast cancer sub-types and stem-like cells. PLoS One, 8, 67811. https://doi.org/10.1371/journal.pone.0067811
  19. Lammi L, Arte S, Somer M, et al (2004). Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet, 74, 1043-50. https://doi.org/10.1086/386293
  20. Lehmann BD, Bauer JA, Chen X, et al (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest, 121, 2750-67. https://doi.org/10.1172/JCI45014
  21. Letra A, Menezes R, Granjeiro JM, et al (2009). AXIN2 and CDH1 polymorphisms, tooth agenesis, and oral clefts. Birth Defects Res A Clin Mol Teratol, 85, 169-73. https://doi.org/10.1002/bdra.20489
  22. Li J, Sheng C, Li W, et al (2014). Protein phosphatase-2A is downregulated in patients within clear cell renal cell carcinoma. Int J Clin Exp Pathol, 7, 1147-53.
  23. Lustig B, Jerchow B, Sachs M, et al (2002). Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol, 22, 1184-93. https://doi.org/10.1128/MCB.22.4.1184-1193.2002
  24. MacDonald BT, Tamai K, He X (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17, 9-26. https://doi.org/10.1016/j.devcel.2009.06.016
  25. Moon RT, Kohn AD, De Ferrari GV, et al (2004). WNT and betacatenin signalling: diseases and therapies. Nat Rev Genet, 5, 691-701. https://doi.org/10.1038/nrg1427
  26. Mosimann C, Hausmann G, Basler K (2009). Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol, 10, 276-86. https://doi.org/10.1038/nrm2654
  27. Mostowska A, Biedziak B, Jagodzinski PP (2006). Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis. J Hum Genet, 51, 262-6. https://doi.org/10.1007/s10038-005-0353-6
  28. Mostowska A, Pawlik P, Sajdak S, et al (2014). An analysis of polymorphisms within the Wnt signaling pathway in relation to ovarian cancer risk in a Polish population. Mol Diagn Ther, 18, 85-91. https://doi.org/10.1007/s40291-013-0059-y
  29. Nelson S, Nathke IS (2013). Interactions and functions of the adenomatous polyposis coli (APC) protein at a glance. J Cell Sci, 126, 873-7. https://doi.org/10.1242/jcs.100479
  30. Pedace L, Castiglia D, De Simone P, et al (2011). AXIN2 germline mutations are rare in familial melanoma. Genes Chromosomes Cancer, 50, 370-3. https://doi.org/10.1002/gcc.20855
  31. Pinarbasi E, Gunes EG, Pinarbasi H, et al (2011). AXIN2 polymorphism and its association with prostate cancer in a Turkish population. Med Oncol, 28, 1373-8. https://doi.org/10.1007/s12032-010-9588-y
  32. Polakis P (2007). The many ways of Wnt in cancer. Curr Opin Genet Dev, 17, 45-51. https://doi.org/10.1016/j.gde.2006.12.007
  33. Rennoll SA, Konsavage WM, Jr., Yochum GS (2014). Nuclear AXIN2 represses MYC gene expression. Biochem Biophys Res Commun, 443, 217-22. https://doi.org/10.1016/j.bbrc.2013.11.089
  34. Rubinfeld B, Robbins P, El-Gamil M, et al (1997). Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science, 275, 1790-2. https://doi.org/10.1126/science.275.5307.1790
  35. Sablina AA, Chen W, Arroyo JD, et al (2007). The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell, 129, 969-82. https://doi.org/10.1016/j.cell.2007.03.047
  36. Salahshor S, Woodgett JR (2005). The links between axin and carcinogenesis. J Clin Pathol, 58, 225-36. https://doi.org/10.1136/jcp.2003.009506
  37. Santos RA, Teixeira AC, Mayorano MB, et al (2010). Basal levels of DNA damage detected by micronuclei and comet assays in untreated breast cancer patients and healthy women. Clin Exp Med, 10, 87-92. https://doi.org/10.1007/s10238-009-0079-4
  38. Schmittgen TD, Livak KJ (2008). Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc, 3, 1101-8. https://doi.org/10.1038/nprot.2008.73
  39. Srivastava M, Khurana P, Sugadev R (2012). Lung cancer signature biomarkers: tissue specific semantic similarity based clustering of digital differential display (DDD) data. BMC Res Notes, 5, 617. https://doi.org/10.1186/1756-0500-5-617
  40. Stamos JL, Weis WI (2013). The beta-catenin destruction complex. Cold Spring Harb Perspect Biol, 5, 7898.
  41. Suraweera N, Robinson J, Volikos E, et al (2006). Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines. Int J Cancer, 119, 1837-42. https://doi.org/10.1002/ijc.22046
  42. Teixeira AC, Dos Santos RA, Poersch A, et al (2009). DNA repair in Etoposide-induced DNA damage in lymphocytes of breast cancer patients and healthy women. Int J Clin Exp Med, 2, 280-8.
  43. Tudoran O, Virtic O, Balacescu L, et al (2014). Differential peripheral blood gene expression profile based on her2 expression on primary tumors of breast cancer patients. PLoS One, 9, 102764. https://doi.org/10.1371/journal.pone.0102764
  44. Wang X, Goode EL, Fredericksen ZS, et al (2008). Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 17, 2101-8. https://doi.org/10.1158/1055-9965.EPI-08-0134
  45. Westermarck J, Hahn WC (2008). Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med, 14, 152-60. https://doi.org/10.1016/j.molmed.2008.02.001
  46. Willert K, Shibamoto S, Nusse R (1999). Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev, 13, 1768-73. https://doi.org/10.1101/gad.13.14.1768
  47. Xie HL, Chen ZC, He CM, et al (2003). [Cloning and expression analysis of lung carcinoma related gene HLCDG1]. Ai Zheng, 22, 1014-7.
  48. Yook JI, Li XY, Ota I, et al (2006). A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol, 8, 1398-406. https://doi.org/10.1038/ncb1508

Cited by

  1. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer vol.156, pp.2, 2016, https://doi.org/10.1007/s10549-016-3746-7
  2. High-order gene interactions between the genetic polymorphisms in Wnt and AhR pathway in modulating lung cancer susceptibility vol.14, pp.6, 2017, https://doi.org/10.2217/pme-2017-0018
  3. Molecular regulation and pharmacological targeting of the β-catenin destruction complex vol.174, pp.24, 2017, https://doi.org/10.1111/bph.13922
  4. gene and lung cancer risk in North Indian population: A multiple interaction analysis vol.39, pp.4, 2017, https://doi.org/10.1177/1010428317695533
  5. Polymorphisms and Their Association with Colorectal Cancer in Mexican Patients vol.20, pp.8, 2016, https://doi.org/10.1089/gtmb.2016.0026