Hostname: page-component-5d59c44645-kw98b Total loading time: 0 Render date: 2024-02-20T16:07:25.867Z Has data issue: false hasContentIssue false

Investigation of Two Wnt Signalling Pathway Single Nucleotide Polymorphisms in a Breast Cancer-Affected Australian Population

Published online by Cambridge University Press:  21 February 2012

Plamena N. Gabrovska
Genomics Research Centre, Griffith Health Institute, Griffith University, Australia
Robert A. Smith
Genomics Research Centre, Griffith Health Institute, Griffith University, Australia
Larisa M. Haupt
Genomics Research Centre, Griffith Health Institute, Griffith University, Australia
Lyn R. Griffiths*
Genomics Research Centre, Griffith Health Institute, Griffith University, Australia
ADDRESS FOR CORRESPONDENCE: Professor Lyn Griffiths, Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast campus, Parklands Drive, Southport QLD 4222, Australia. E-mail:


Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Previously, we identified two Wnt signaling pathway-implicated genes, PPP3CA and MARK4, as having a role in more aggressive and potentially metastatic breast tumors. In this study, we examined two SNPs within PPP3CA and MARK4 in an Australian case-control study population for a potential role in human breast cancers. 182 cases and 180 controls were successfully genotyped for the PPP3CA SNP (rs2850328) and 182 cases and 177 controls were successfully genotyped for the MARK4 SNP (rs2395) using High Resolution Melt (HRM) analysis. Genotypes of randomly selected samples for both SNPs were validated by dye terminator sequencing. Chi-square tests were performed to determine any significant differences in the genotype and allele frequencies between the cases and controls. Chi-square analysis showed no statistically significant difference (ρ > .05) for genotype frequencies between cases and controls for rs2850328 (χ2 = 1.2, p = .5476) or rs2395 (χ2 = .3, p = .8608). Similarly, no statistical difference was observed for allele frequencies for rs2850328 (χ2 = .68, p = .4108) or rs2395 (χ2 = .02, p = .893). Even though an association of the polymorphisms rs2850328 and rs2395 and breast cancer was not detected in our case-control study population, other variants within the PPP3CA and MARK4 genes may still be associated with breast cancer, as both genes are implicated with processes involved in the disease as well as their mutual partaking in the Wnt signaling pathway.

Copyright © Cambridge University Press 2011


Brennan, K. R., & Brown, A. M. (2004). Wnt proteins in mammary development and cancer. Journal of Mammary Gland Biology and Neoplasia, 9, 119131.Google Scholar
Cadigan, K. M., & Nusse, R. (1997). Wnt signaling: A common theme in animal development. Genes and Development, 11, 32863305.Google Scholar
Chiocco, M. J., Zhu, X., Walther, D., Pletnikova, O., Troncoso, J. C., Uhl, G. R., & Liu, Q. R. (2010). Fine mapping of calcineurin (PPP3CA) gene reveals novel alternative splicing patterns, association of 5'UTR trinucleotide repeat with addiction vulnerability, and differential isoform expression in Alzheimer's disease. Substance Use and Misuse, 45, 18091826.Google Scholar
Dash, R., Su, Z. Z., Lee, S. G., Azab, B., Boukerche, H., Sarkar, D., & Fisher, P. B. (2010). Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1. Oncogene, 29, 44124423.Google Scholar
Ebneth, A., Drewes, G., Mandelkow, E. M., & Mandelkow, E. (1999). Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells. Cell Motility and the Cytoskeleton, 44, 209224.Google Scholar
Faul, F., Erdfelder, E., Lang, A. G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175191.Google Scholar
Gabrovska, P. N., Smith, R. A., Tiang, T., Weinstein, S. R., Haupt, L. M. & Griffiths, L. R. (2011). Development of an eight gene expression profile implicating human breast tumours of all grade. Molecular Biology Reports.Google Scholar
Guerini, D., & Klee, C. B. (1989). Cloning of human calcineurin A: Evidence for two isozymes and identification of a polyproline structural domain. Proceedings of the National Academy of Sciences USA, 86, 91839187.Google Scholar
Howe, L. R., & Brown, A. M. (2004). Wnt signaling and breast cancer. Cancer Biology and Therapy, 3, 3641.Google Scholar
Kato, T., Satoh, S., Okabe, H., Kitahara, O., Ono, K., Kihara, C., Tanaka, T., Tsunoda, T., Yamaoka, Y., Nakamura, Y., & Furukawa, Y. (2001). Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia, 3, 49.Google Scholar
Kinzler, K. W., & Vogelstein, B. (1996). Life (and death) in a malignant tumor. Nature, 379, 1920.Google Scholar
Lea, R. A., Ovcaric, M., Sundholm, J., MacMillan, J., Griffiths, L. R. (2004). The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Medicine, 2, 3.Google Scholar
Lea, R. A., Selvey, S., Ashton, K. J., Curran, J. E., Gaffney, P. T., Green, A. C., & Griffiths, L. R. (1998). The null allele of GSTM1 does not affect susceptibility to solar keratoses in the Australian white population. Journal of the American Academy of Dermatology, 38, 631633.Google Scholar
Sampath, D., Zhu, Y., Winneker, R. C., & Zhang, Z. (2001). Aberrant expression of Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, and dysregulation by 17 beta-estradiol and basic fibroblast growth factor in human uterine leiomyomas. Journal of Clinical Endocrinology and Metabolism, 86, 17071715.Google Scholar
Sun, T. Q., Lu, B., Feng, J. J., Reinhard, C., Jan, Y. N., Fantl, W. J., & Williams, L. T. (2001). PAR-1 is a dishevelled-associated kinase and a positive regulator of Wnt signalling. Nature Cell Biology, 3, 628636.Google Scholar
Trinczek, B., Brajenovic, M., Ebneth, A., & Drewes, G. (2004). MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. The Journal of Biological Chemistry, 279, 59155923.Google Scholar
Tsai, M. S., Bogart, D. F., Castaneda, J. M., Li, P., & Lupu, R. (2002). Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene, 21, 81788185.Google Scholar
Vellon, L., Menendez, J. A., & Lupu, R. (2005). Alpha Vbeta3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene, 24, 37593773.Google Scholar
Xie, D., Nakachi, K., Wang, H., Elashoff, R., & Koeffler, H. P. (2001). Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Research, 61, 89178923.Google Scholar
Zhang, Z., Hartmann, H., Do, V. M., Abramowski, D., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., van de Wetering, M., Clevers, H., Saftig, P., De Strooper, B., He, X., & Yankner, B. A. (1998). Destabilization of betacatenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature, 395, 698702.Google Scholar