Browse > Article
http://dx.doi.org/10.7314/APJCP.2015.16.16.7277

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

Aristizabal-Pachon, Andres Felipe (Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo)
Carvalho, Thais Inacio (Department of Oncology, Hospital Santa Casa of Ribeirao Preto)
Carrara, Helio Humberto (Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo)
Andrade, Jurandyr (Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo)
Takahashi, Catarina Satie (Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.16, no.16, 2015 , pp. 7277-7284 More about this Journal
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
AXIN2; beta-catenin destruction complex; breast cancer; SNP; RFLP-PCR; gene expression; RT-qPCR;
Citations & Related Records
연도 인용수 순위
  • Reference
1 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.
2 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.   DOI
3 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.   DOI
4 Klarmann GJ, Decker A, Farrar WL (2008). Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics, 3, 59-63.   DOI
5 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.   DOI
6 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.   DOI
7 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.   DOI
8 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.   DOI
9 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.
10 Rennoll SA, Konsavage WM, Jr., Yochum GS (2014). Nuclear AXIN2 represses MYC gene expression. Biochem Biophys Res Commun, 443, 217-22.   DOI
11 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.   DOI
12 Sablina AA, Chen W, Arroyo JD, et al (2007). The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell, 129, 969-82.   DOI
13 Salahshor S, Woodgett JR (2005). The links between axin and carcinogenesis. J Clin Pathol, 58, 225-36.   DOI
14 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.   DOI
15 Schmittgen TD, Livak KJ (2008). Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc, 3, 1101-8.   DOI
16 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.   DOI
17 Stamos JL, Weis WI (2013). The beta-catenin destruction complex. Cold Spring Harb Perspect Biol, 5, 7898.
18 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.   DOI
19 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.
20 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.   DOI
21 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.   DOI
22 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.   DOI
23 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.   DOI
24 Clevers H, Nusse R (2012). Wnt/beta-catenin signaling and disease. Cell, 149, 1192-205.   DOI
25 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.   DOI
26 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.   DOI
27 Gunes EG, Pinarbasi E, Pinarbasi H, et al (2009). Strong association between lung cancer and the AXIN2 polymorphism. Mol Med Report, 2, 1029-35.
28 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.   DOI
29 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.   DOI
30 Howe LR, Brown AM (2004). Wnt signaling and breast cancer. Cancer Biol Ther, 3, 36-41.   DOI
31 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.   DOI
32 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.   DOI
33 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.   DOI
34 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.   DOI
35 MacDonald BT, Tamai K, He X (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17, 9-26.   DOI
36 Moon RT, Kohn AD, De Ferrari GV, et al (2004). WNT and betacatenin signalling: diseases and therapies. Nat Rev Genet, 5, 691-701.   DOI
37 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.   DOI
38 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.   DOI
39 Nelson S, Nathke IS (2013). Interactions and functions of the adenomatous polyposis coli (APC) protein at a glance. J Cell Sci, 126, 873-7.   DOI
40 Pedace L, Castiglia D, De Simone P, et al (2011). AXIN2 germline mutations are rare in familial melanoma. Genes Chromosomes Cancer, 50, 370-3.   DOI
41 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.   DOI
42 Polakis P (2007). The many ways of Wnt in cancer. Curr Opin Genet Dev, 17, 45-51.   DOI
43 Willert K, Shibamoto S, Nusse R (1999). Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev, 13, 1768-73.   DOI
44 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.   DOI
45 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.   DOI
46 Westermarck J, Hahn WC (2008). Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med, 14, 152-60.   DOI
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.   DOI