Carcinogenesis Advance Access originally published online on June 10, 2008
Carcinogenesis 2008 29(7):1394-1399; 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), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
2 Department of Oncology, Norrlands University Hospital, 90187 Umeå, Sweden
3 Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, 90185 Umeå, Sweden
4 Center for Family and Community Medicine, Karolinska Institute, 14183 Huddinge, Sweden
5 Present address: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, LHRRB R505, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +49 6221 421803; Fax: +49 6221 421810; Email: a.foersti{at}dkfz.de
Integrins control the cell attachment to the extracellular matrix 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. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and 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 oestrogen receptor-negative tumours [odds ratio 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 with the wild-type genotype carriers (hazard ratio 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.
Abbreviations: BC, breast cancer; CI, confidence interval; ECM, extracellular matrix; ER, oestrogen receptor; HR, hazard ratio; miRNA, microRNA; mRNA, messenger RNA; OR, odds ratio; SNP, single-nucleotide polymorphism; UTR, untranslated region; WT, wild-type
Received February 28, 2008; revised April 16, 2008; accepted May 17, 2008.
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