Carcinogenesis Advance Access published online on June 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn126
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Polymorphisms in predicted microRNA binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker
1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Department of Oncology, Norrlands University Hospital, Umeå, Sweden
3 Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Sweden
4 Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden
Correspondence and reprint request: Annika Brendle, Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany, Phone: +49-6221-421804, Fax: +49-6221-421810, email: A.Vaclavicek{at}dkfz.de
Integrins control the cell attachment to the extracellular matrix (ECM) and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions (UTRs). We examined the effect of single nucleotide polymorphisms (SNPs) in predicted miRNA taget sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4, ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and estrogen receptor negative (ER-) tumours (odds ratio [OR] 2.09, 95% confidence intervals [CIs] 1.19-3.67). The same SNP was associated with survival. The A allele carriers had a worse survival compared to the wild type genotype carriers (hazard ratio [HR] 2.11 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.
* Current address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, LHRRB R505, Boston MA USA
Received February 28, 2008; revised April 16, 2008; accepted May 17, 2008.
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