Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.
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ABSTRACT:
SUBMITTER: Meyer KB
PROVIDER: S-EPMC2365982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION: SNPs rs2981582 and rs2981578, located in a linkage disequilibrium block (LD block) within intron 2 of the fibroblast growth factor receptor 2 gene (FGFR2), are associated with a mildly increased breast cancer risk. Allele-specific regulation of FGFR2 mRNA expression has been reported previously, but the molecular basis for the association of these variants with breast cancer has remained elusive to date. METHODS: mRNA levels of FGFR2 and three fibroblast growth factor genes (FGFs) were measured in primary fibroblast and epithelial cell cultures from 98 breast cancer patients and correlated to their rs2981578 genotype. The phosphorylation levels of downstream FGFR2 targets, FGF receptor substrate 2? (FRS2?) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), were quantified in skin fibroblasts exposed to FGF2. Immunohistochemical markers for angiogenesis and lymphocytic infiltrate were semiquantitatively assessed in 25 breast tumors. RESULTS: The risk allele of rs2981578 was associated with increased FGFR2 mRNA levels in skin fibroblasts, but not in skin epithelial cell cultures. FGFR2 mRNA levels in skin fibroblasts and breast fibroblasts correlated strongly in the patients from whom both cultures were available. Tumor-derived fibroblasts expressed, on average, eight times more FGFR2 mRNA than the corresponding fibroblasts from normal breast tissue. Fibroblasts with higher FGFR2 mRNA expression showed more FRS2? and ERK1/2 phosphorylation after exposure to FGF2. In fibroblasts, higher FGFR2 expression correlated with higher FGF10 expression. In 25 breast tumors, no associations between breast tumor characteristics and fibroblast FGFR2 mRNA levels were found. CONCLUSIONS: The influence of rs2981578 genotypes on FGFR2 mRNA expression levels is cell type-dependent. Expression differences correlated well with signaling levels of the FGFR2 pathway. Our results suggest that the increased breast cancer risk associated with SNP rs2981578 is due to increased FGFR2 signaling activity in stromal fibroblasts, possibly also involving paracrine FGF10 signaling.
| S-EPMC3236336 | biostudies-literature
Project description:BACKGROUND: In a cancer cell the number of copies of a locus may vary due to amplification and deletion and these variations are denoted as copy number alterations (CNAs). We focus on the disparity of CNAs in tumour samples, which were compared to those in blood in order to identify the directional loss of heterozygosity. METHODS: We propose a numerical algorithm and apply it to data from the Illumina 109K-SNP array on 112 samples from breast cancer patients. B-allele frequency (BAF) and log R ratio (LRR) of Illumina were used to estimate Euclidian distances. For each locus, we compared genotypes in blood and tumour for subset of samples being heterozygous in blood. We identified loci showing preferential disparity from heterozygous toward either the A/B-allele homozygous (allelic disparity). The chi-squared and Cochran-Armitage trend tests were used to examine whether there is an association between high levels of disparity in single nucleotide polymorphisms (SNPs) and molecular, clinical and tumour-related parameters. To identify pathways and network functions over-represented within the resulting gene sets, we used Ingenuity Pathway Analysis (IPA). RESULTS: To identify loci with a high level of disparity, we selected SNPs 1) with a substantial degree of disparity and 2) with substantial frequency (at least 50% of the samples heterozygous for the respective locus). We report the overall difference in disparity in high-grade tumours compared to low-grade tumours (p-value < 0.001) and significant associations between disparity in multiple single loci and clinical parameters. The most significantly associated network functions within the genes represented in the loci of disparity were identified, including lipid metabolism, small-molecule biochemistry, and nervous system development and function. No evidence for over-representation of directional disparity in a list of stem cell genes was obtained, however genes appeared to be more often altered by deletion than by amplification. CONCLUSIONS: Our data suggest that directional loss and amplification exist in breast cancer. These are highly associated with grade, which may indicate that they are enforced with increasing number of cell divisions. Whether there is selective pressure for some loci to be preferentially amplified or deleted remains to be confirmed.
| S-EPMC3337547 | biostudies-literature
Project description:Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (P trend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer.
| S-EPMC6172344 | biostudies-literature
Project description:The association between fibroblast growth factor receptor 2 (FGFR2) polymorphism and breast cancer (BC) susceptibility remains inconclusive. The purpose of this systematic review was to evaluate the relationship between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and BC risk. PubMed, Web of science and the Cochrane Library databases were searched before October 11, 2015 to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Sensitivity and subgroup analyses were conducted. Thirty-five studies published from 2007 to 2015 were included in this meta-analysis. The pooled results showed that there was significant association between all the 3 variants and BC risk in any genetic model. Subgroup analysis was performed on rs2981582 and rs2420946 by ethnicity and Source of controls, the effects remained in Asians, Caucasians, population-based and hospital-based groups. We did not carryout subgroup analysis on rs2981578 for the variant included only 3 articles. This meta-analysis of case-control studies provides strong evidence that FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphisms were significantly associated with the BC risk. For rs2981582 and rs2420946, the association remained significant in Asians, Caucasians, general populations and hospital populations. However, further large scale multicenter epidemiological studies are warranted to confirm this finding and the molecular mechanism for the association need to be elucidated further.
| S-EPMC5356895 | biostudies-literature
Project description:BackgroundLysosome-associated protein transmembrane 4 beta (LAPTM4B) has two alleles named LAPTM4B*1 and LAPTM4B*2. Allele *1 contains only one copy of a 19-bp sequence at the 5'UTR in the first exon, whereas this sequence of allele*2 is duplicated and arrayed as a tandem repeat. Previous studies revealed that LAPTM4B polymorphisms contribute to the risk of certain types of cancers. This study aimed to investigate the polymorphism of LAPTM4B in breast cancer by analysis the correlation of LAPTM4B genotype with breast cancer susceptibility, clinicopathologic features and prognosis.MethodsGenotyping of the LAPTM4B polymorphism was determined by PCR method. The expression levels of LAPTM4B in breast cancer tissues and breast cancer cell lines were determined by quantitative reverse-transcription PCR (qRT-PCR) analysis. The correlation of LAPTM4B genotype with clinicopathologic parameters and prognosis were assessed statistically.ResultsThe results of qRT-PCR analysis indicated that LAPTM4B*2 was associated with the higher level of LAPTM4B expression compared with the LAPTM4B*1 in both breast cancer cell lines and breast cancer tissues. We found that LAPTM4B*2 was associated with an increased risk for breast cancer. LAPTM4B*2 was significantly associated with higher histopathologic grade, lymph node metastasis and poor prognosis.ConclusionLAPTM4B*2 is a risk factor associated with breast cancer susceptibility and poor prognosis. LAPTM4B*2 may be a potential predicative marker for the susceptibility, progression and metastasis of breast cancer.
| S-EPMC3440355 | biostudies-literature
Project description:In this study, expression of the SPC25 gene was characterized in breast cancer (BC), and its effects on BC development and progression, functions in BC cells, and potential underlying mechanisms were examined. Data from TCGAportal and FIREBROWSE indicated that SPC25 was upregulated in BC tissues compared to normal tissues, and CANCERTOOL indicated that higher SPC25 mRNA levels were associated with increased probability of recurrence and poorer survival in BC patients. BC patients with higher SPC25 expression displayed shorter distant metastasis-free survival, relapse-free survival, and overall survival. Colony formation and CCK-8 experiments confirmed that SPC25 promoted proliferation of BC cells. Single-cell analysis indicated that SPC25 is associated with cell cycle regulation, DNA damage and repair, and BC cell proliferation. SPC25 knockdown suppressed proliferation of BC cells. MiRNAs, circRNAs, RNA-binding proteins, transcription factors, and immune factors that might interact with SPC25 mRNA to promote BC were also identified. These findings suggest that SPC25 levels are higher in more malignant BC subtypes and are associated with poor prognosis in BC patients. In addition, DNA methyltransferase inhibitor and transcription factors inhibitor treatments targeting SPC25 might improve survival in BC patients.
| S-EPMC6710047 | biostudies-other
Project description:Obesity condition confers risks to breast cancer development and progression, and several reports indicate that the adipokine leptin, whose synthesis and plasma levels increase with obesity, might play an important role in modulating breast cancer cell phenotype. Functional crosstalk occurring between leptin and different signaling molecules contribute to breast carcinogenesis. In this study, we show, in different human breast cancer cell lines, that leptin enhanced the expression of a chaperone protein Hsp90 resulting in increased HER2 protein levels. Silencing of Hsp90 gene expression by RNA interference abrogated leptin-mediated HER2 up-regulation. Leptin effects were dependent on JAK2/STAT3 activation, since inhibition of this signaling cascade by AG490 or ectopic expression of a STAT3 dominant negative abrogated leptin-induced HER2 and Hsp90 expressions. Functional experiments showed that leptin treatment significantly up-regulated human Hsp90 promoter activity. This occurred through an enhanced STAT3 transcription factor binding to its specific responsive element located in the Hsp90 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Analysis of HER2, Akt and MAPK phosphorylation levels revealed that leptin treatment amplified the responsiveness of breast cancer cells to growth factor stimulation. Furthermore, we found that long-term leptin exposure reduced sensitivity of breast cancer cells to the antiestrogen tamoxifen. In the same experimental conditions, the combined treatment of tamoxifen with the Hsp90 inhibitor 17-AAG completely abrogated leptin-induced anchorage-independent breast cancer cell growth. In conclusion, our results highlight, for the first time, the ability of the adipocyte-secreted factor leptin to modulate Hsp90/HER2 expressions in breast cancer cells providing novel insights into the molecular mechanism linking obesity to breast cancer growth and progression.
| S-EPMC5528468 | biostudies-other
Project description:It is known that FGFR2 gene variations confer a risk for breast cancer. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5-10% of breast tumors. In our study, we sequenced the most important coding regions of FGFR2 in somatic tumor tissue of 140 sporadic breast cancer patients and performed MLPA analysis to detect copy number variations in FGFR2 and FGF10. We identified one somatic heterozygous missense mutation, p.K660N (c.1980G>C), within the tyrosine kinase domain of FGFR2 in tumor tissue of a sporadic breast cancer patient, which is likely mediated by the FGFR2-IIIb isoform. The presence of wild type and mutated alleles in equal quantities suggests that the mutation has driven clonal amplification of mutant cells. We have analyzed the tyrosine kinase activity of p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C, after expression in HEK293 cells and demonstrated that the intrinsic tyrosine kinase activity of both mutant proteins is strongly increased resulting in elevated phosphorylation and activity of downstream effectors. To our knowledge, this is the first report of functional analysis of somatic breast cancer mutations in FGFR2 providing evidence for the activating nature of FGFR2-mediated signalling in the pathogenesis of breast cancer.
| S-EPMC3603931 | biostudies-literature
Project description:We integrated data obtained from HIV-1 genome-wide association studies with T cell-derived epigenome data and found that the noncoding intergenic variant rs4349147, which is statistically associated with HIV-1 acquisition, is located in a CD4+ T cell-specific deoxyribonuclease I hypersensitive region, suggesting regulatory potential for this variant. Deletion of the rs4349147 element in Jurkat cells strongly reduced expression of interleukin-32 (IL-32), approximately 10-kb upstream, and chromosome conformation capture assays identified a chromatin loop between rs4349147 and the IL-32 promoter validating its function as a long-distance enhancer. We generated single rs4349147-A or rs4349147-G allele clones and demonstrated that IL-32 enhancer activity and interaction with the IL-32 promoter are strongly allele dependent; rs4349147 -/A cells display reduced IL-32 expression and altered chromatin conformation as compared to rs4349147 G/- cells. Moreover, RNA sequencing demonstrated that rs4349147 G/- cells express a lower relative ratio of IL-32? to non-? isoforms than rs4349147 -/A cells and display increased expression of lymphocyte activation factors rendering them more prone to infection with HIV-1. In agreement, in primary CD4+ T cells, both treatment with recombinant IL-32? (rIL-32?) but not rIL-32?, and exogenous lentiviral overexpression of IL-32? or IL-32? but not IL-32? resulted in a proinflammatory T cell cytokine environment concomitant with increased susceptibility to HIV infection. Our data demonstrate that rs4349147-G promotes transcription of non-IL-32? isoforms, generating a proinflammatory environment more conducive to HIV infection. This study provides a mechanistic link between a HIV-associated noncoding DNA variant and the expression of different IL-32 isoforms that display discrete anti-HIV properties.
| S-EPMC5833994 | biostudies-literature
Project description:Fibroblast growth factor receptor 2 is a protein encoded by FGFR2 gene and plays an important role in cellular growth. This study was conducted to investigate a potential association of FGFR2 rs2981582 with breast cancer. DNA was obtained from 137 Formalin-fixed, paraffin-embedded tumors and 98 normal breast tissue samples. Genotypes were carried out with PCR-RFLP. The odds ratio and 95% confidence interval (CI) were used to evaluate the power of the associations. A significant association between FGFR2 rs2981582 C allele and susceptibility to breast cancer was found (p-value < 0.0001, Odds Ratio = 2.3, %95 CI (1.5–3.0). No significant differences in FGFR2 rs2981582 genotypes and alleles distribution among breast patients with different hormonal receptor status (p > 0.05) were detected. However, a significant difference was found in genotypes and alleles distribution in ER+, PR- and HER2 between breast cancer cases and controls. This study showed an association of FGFR2 rs2981582T/C with breast cancer in Saudi women, further large study is required to validate the results.
| S-EPMC8568711 | biostudies-literature