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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.

Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor prognosis in breast cancer. We examined whether genetic variation in the genes of the uPA system affect breast cancer susceptibility and prognosis. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in six genes of the uPA system in 959 Swedish breast cancer patients with detailed clinical data and up to 15 years of follow-up together with 952 matched controls. We used the unconditional logistic regression models to evaluate the associations between genotypes and breast cancer risk and tumor characteristics. The Kaplan-Meier method was used to estimate the survival probabilities; the log-rank test was used to test differences between subgroups. None of the SNPs conferred an increased breast cancer risk, but correlation with some traditional prognostic factors was observed for several SNPs. Most importantly, we identified the -675 4G/5G SNP in the PAI-1 gene as a promising prognostic biomarker for breast cancer. Compared to the 4G/4G and 4G/5G genotypes 5G/5G homozygosity correlated significantly with worse survival (RR 2.04, 95% CI 1.45-2.86, P<0.001), especially in patients with more aggressive tumors. 5G/5G homozygotes were also the group with worse survival among lymph node negative cases. Our finding suggests that genotyping PAI-1 -675 4G/5G may help in clinical prognosis of breast cancer.

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det

Paper I & II: CDH1 germline mutations predispose individuals to diffuse gastric cancer, but its role in breast cancer is less clear. Somatic CDH1 mutations were reported to be frequent in lobular tumours (ILC), but they have not been found in ductal carcinomas (IDC). To define the role of CDH1 in breast cancer, we used denaturing high performance liquid chromatography to screen a series of breast cancer samples for mutations. Somatic mutations were detected in 4 of 83 IDC (5%) and 3 of 25 ILC (12%). No germline mutation was found in 19 familial breast cancer patients that showed loss of heterozygosity (LOH) at 16q24, in 12 cases from 10 families with breast, gastric and colon cancer and in 13 familial lobular breast tumours. Another somatic mutation was detected in one of the familial breast cancer patient with both ductal and lobular foci. Putative breast cancer risk conferred by the promoter polymorphism -161C-A of CDH1 or 1774G-A (Ala592Thr) was also analyzed in case-control studies. No significant difference in allelic frequency was found between the breast cancer patients and controls for either polymorphism. A novel promoter polymorphism was identified at position -152 with a similar frequency of the rare C allele in both breast cancer patients and controls. Transient transfection assay using constructs containing -16IC/-152C or -161A/-152T showed only a slight decrease of the transcription activity as compared to the wild type constructs carrying -161C/152T. We conclude that CDH1 is not a prominent lowpenetrance gene in breast cancer, but CDH1 mutations contribute to the progression of both lobular and ductal tumours. Paper III: BACH1, a gene located in 17q22 and encoding a protein directly interacting with BRCA1, was suggested to be a candidate gene for breast cancer susceptibility. Using PCR-SSCP, we screened for germline BACH] mutations with 29 breast cancer families linked to 17q22 and additional 95 familial breast cancer cases, which were all without det