Loss of SFRP1 is associated with breast cancer progression in early stage tumors

Freie Universität Berlin, Berlin, Germany.
International Journal of Oncology (Impact Factor: 3.03). 10/2004; 25(3):641-9. DOI: 10.3892/ijo.25.3.641
Source: PubMed


Aberrant activation of the Wnt signaling pathway plays an important role in the development of solid tumors such as breast and colon cancer. Secreted Frizzled-related protein 1 (SFRP1) is a negative regulator of the Wnt pathway. It has been described that SFRP1 mRNA is strongly down-regulated in breast cancer and a putative tumor suppressor function has been postulated. We have generated and characterized an SFRP1 specific antibody to analyze its expression on protein level and to investigate the association of SFRP1 expression with clinicopathological parameters and patient survival. Analysis of >2000 invasive breast tumors and 56 carcinoma in situ revealed similar frequencies of SFRP1 loss in these tumors (46% and 43% respectively). Therefore, we propose that loss of SFRP1 expression is an early event in breast tumorigenesis. SFRP1 expression was inversely correlated with tumor stage (p<0.001) but not with tumor grade (p=0.14) or lymph node status (p=0.84). Performing a multivariate analysis we could confirm the association between tumor stage and SFRP1 expression (p=0.029). In particular, loss of SFRP1 expression in early stage breast tumors (pT1) was associated with poor prognosis (p=0.04). In conclusion, expression of SFRP1 is commonly lost in breast cancer. SFRP1 expression might be useful as a novel prognostic marker in early stage breast cancer.

18 Reads
  • Source
    • "Intermediate " v.s. " Poor " Among these ten genes, six of them, GDF5, TCF7L1, PAPSS1, SFRP1, GABRP, TGFB1, have been previously studied and verified in the literature that are associated with the breast cancer (See Margheri et al. (2012), Shy et al. (2013), Xu et al. (2012), Klopocki et al. (2004), Zafrakas et al. (2006), and Ghellal et al. (2000), respectively). Take for example GDF5 and TCF7L1, the overproduction of Transforming growth factor beta-1 (TGFβ), a multifunctional cytokine, is an important characteristic of late tumor progression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Motivated by differential co-expression analysis in genomics, we consider in this paper estimation and testing of high-dimensional differential correlation matrices. An adaptive thresholding procedure is introduced and theoretical guarantees are given. Minimax rate of convergence is established and the proposed estimator is shown to be adaptively rate-optimal over collections of paired correlation matrices with approximately sparse differences. Simulation results show that the procedure significantly outperforms two other natural methods that are based on separate estimation of the individual correlation matrices. The procedure is also illustrated through an analysis of a breast cancer dataset, which provides evidence at the gene co-expression level that several genes, of which a subset has been previously verified, are associated with the breast cancer. Hypothesis testing on the differential correlation matrices is also considered. A test, which is particularly well suited for testing against sparse alternatives, is introduced. In addition, other related problems, including estimation of a single sparse correlation matrix, estimation of the differential covariance matrices, and estimation of the differential cross-correlation matrices, are also discussed.
    Preview · Article · Aug 2014 · Journal of Multivariate Analysis
  • Source
    • "Immunohistochemistry was performed on formalin-fixed, paraffin-embedded (FFPE-) 4 μm TMA sections of tumour tissue specimen transferred to glass slides. TMA construction was performed as described previously [24,25]. TMAs were stained with monoclonal mouse anti-MTUS1 antibody (Abnova, Heidelberg/Germany, overnight, RT). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer. MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured. MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability. MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.
    Full-text · Article · Mar 2014 · BMC Cancer
  • Source
    • "They showed that mammary epithelial cells from SFRP1 knock-out mice had a decreased expression of p53, caspase-3, along with lesser DNA fragmentation in response to DNA damage and a recombinant expression of SFRP1 could elevate the levels of pro-apoptotic and p53 mediated gene expression. In another study, loss of SFRP1 expression was thought to be an early event in breast tumourigenesis [57], with its expression inversely correlated with tumour stage (p<0.001) but not tumour grade or lymph node status. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Wnt (wingless-type) signalling pathway plays an important role in embryonic development, tissue homeostasis, and tumour progression because of its effect on cell proliferation, migration, and differentiation. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signalling that act by binding directly to Wnt ligands or to Frizzled receptors. In recent years, aberrant expression of SFRPs has been reported to be associated with numerous cancers. As gene expression of SFRP members is often lost through promoter hypermethylation, inhibition of methylation through the use of epigenetic modifying agents could renew the expression of SFRP members and further antagonize deleterious Wnt signalling. Several reports have described epigenetic silencing of these Wnt signalling antagonists in various human cancers, suggesting their possible role as tumour suppressors. SFRP family members thus come across as potential tools in combating Wnt-driven tumourigenesis. However, little is known about SFRP family members and their role in different cancers. This review comprehensively covers all the available information on the role of SFRP molecules in various human cancers.
    Full-text · Article · Jan 2014 · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Show more

Similar Publications