TOX3 mutations in breast cancer.
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ABSTRACT:
SUBMITTER: Jones JO
PROVIDER: S-EPMC3777980 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
TOX3 mutations in breast cancer.
Jones James Owain JO Chin Suet-Feung SF Wong-Taylor Li-An LA Leaford Donna D Ponder Bruce A J BA Caldas Carlos C Maia Ana-Teresa AT
PloS one 20130919 9
TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs) in six primary tumours, corresponding to an overall mutation freq ...[more]
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Project description:Genome wide association studies (GWAS) have identified low penetrance and high frequency single nucleotide polymorphisms (SNPs) that contribute to genetic susceptibility of breast cancer. The SNPs at 16q12, close to the TOX3 and CASC16 genes, represent one of the susceptibility loci identified by GWAS, showing strong evidence for breast cancer association across various populations. To examine molecular mechanisms of TOX3 regulation in breast cancer, we investigated both genetic and epigenetic factors using cell lines and datasets derived from primary breast tumors available through The Cancer Genome Atlas (TCGA). TOX3 expression is highly up-regulated in luminal subtype tumors compared to normal breast tissues or basal-like tumors. Expression quantitative trait loci (eQTL) analyses revealed significant associations of rs3803662 and rs4784227 genotypes with TOX3 expression in breast tumors. Bisulfite sequencing of four CpG islands in the TOX3 promoter showed a clear difference between luminal and basal-like cancer cell lines. 5-Aza-2'-deoxycytidine treatment of a basal-like cancer cell line increased expression of TOX3. TCGA dataset verified significantly lower levels of methylation of the promoter in luminal breast tumors with an inverse correlation between methylation and expression of TOX3. Methylation QTL (mQTL) analyses showed a weak or no correlation of rs3803662 or rs4784227 with TOX3 promoter methylation in breast tumors, indicating an independent relationship between the genetic and epigenetic events. These data suggest a complex system of TOX3 regulation in breast tumors, driven by germline variants and somatic epigenetic modifications in a subtype specific manner.
| S-EPMC5091860 | biostudies-literature
Project description:TOX3 is a newly identified gene that has been observed to correlate with breast cancer by genome-wide association studies (GWAS) in recent years. In addition, it has been noted that single-nucleotide polymorphisms (SNPs) in the TOX3 gene have a strong correlation with estrogen receptor (ER)-positive tumors. However, the role of TOX3 in breast carcinoma development is still unclear. There are limited studies on the subject of TOX3 mRNA expression in breast tumors and little information on the variation of TOX3 protein expression in relation to the clinical pathological features in breast cancer and healthy tissues. In this study, we characterize the protein expression of TOX3 in breast tumors with respect to various clinical and pathological characteristics and explore the correlation between TOX3 protein expression and ER-positive tumors. A breast cancer tissue microarray containing 267 human breast tumors and 25 healthy controls, breast cancer cell lines (ZR-75-1, MDA-MB-231, MCF-7 and Bcap-37) with positive or negative ER expression, tumor tissues and matched controls were used to analyze the protein expression levels of TOX3 by immunohistochemistry, western blot analysis and quantitative polymerase chain reaction. Among the 267 breast tumor specimens, ER expression was detected in 66 tumor tissues. The expression levels of TOX3 increased in breast carcinoma tissue compared with controls, and were higher in advanced carcinoma (T3 and T4), lymph node metastases tissues (N2) and stage III tissues. Furthermore, TOX3 protein expression was more intense in ER-positive tumors, but did not demonstrate a statistical significance. However, it was significantly increased in ER-positive breast cancer cell lines (ZR-75-1, MCF-7 and Bcap-37) compared with the MDA-MB-231 cell line, which had ER-negative expression. Our findings provide support to the hypothesis that TOX3 has a strong correlation with the development of breast cancer. The current study is likely to assist in investigating the mechanisms involved in breast cancer development.
| S-EPMC4774471 | biostudies-literature
Project description:The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612); Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 ((95% confidence intervals (CI), 1.10-1.57)) and 1.26 (95% CI, 1.02-1.56), respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer.
| S-EPMC3958841 | biostudies-literature
Project description:BACKGROUND:The rs3803662 single nucleotide polymorphism (SNP) in the TOX3/LOC643714 region was identified as a breast cancer susceptibility genetic variant in recent genome-wide association studies of women of European ancestry and has been replicated in other populations of European ancestry. The position of the causal variant tagged by the rs3803662 marker is still unknown. In fact, because the rs3803662 polymorphism is located between the TOX3 and the LOC643714 loci, it is unclear which gene is the one causally related to the risk of breast cancer. Because linkage disequilibrium blocks are smaller in populations of African ancestry, fine-mapping in African ancestry samples might be an effective approach to narrowing the position of the causal variant(s) in the TOX3/LOC643714 locus. METHODS:We evaluated a total of 60 tagging SNPs throughout the TOX3/LOC643714 region in a nested case-control study of breast cancer within the Black Women's Health Study, which included 906 cases and 1,111 controls. RESULTS:No significant association was found for the rs3803662 SNP. However, four other SNPs (rs3104746, rs3112562, rs3104793, and rs8046994), all of them located in the LOC643714 gene, were associated with risk of breast cancer. The strongest association was observed for rs3104746: each copy of the A-rs3104746 allele was associated with a 23% higher risk of breast cancer (odds ratios, 1.23; 95% confidence intervals, 1.05-1.44; P=0.009). CONCLUSIONS:Our results confirm the association observed in genome-wide association studies of European ancestry populations. IMPACT:The results narrow the locus to a smaller linkage disequilibrium block in the LOC643714 gene.
| S-EPMC2866101 | biostudies-literature
Project description:The associations of SNPs in TOX3 gene with breast cancer risk were investigated by some Genome-wide association studies and epidemiological studies, but the study results were contradictory. To derive a more precise estimate of the associations, we conducted a meta-analysis. ORs with 95% CI were used to assess the strength of association between TOX3 polymorphisms and breast cancer risk in fixed or random effect model. A total of 37 publications with 97275 cases and 128686 controls were identified. We observed that the rs3803662 C > T, rs12443621 A > G and rs8051542 C > T were all correlated with increased risk of breast cancer. In the stratified analyses by ethnicity, significantly elevated risk was detected for all genetic models of the three SNPs in Caucasians. In Asian populations, there were significant associations of rs3803662 and rs8051542 with breast cancer risk. Whereas there was no evidence for statistical significant association between the three SNPs and breast cancer risk in Africans. Additionally, we observed different associations of rs3803662 with breast cancer risk based on different ER subtype and BRCA1/BRCA2 mutation carriers. In conclusion, the meta-analysis suggested that three SNPs in TOX3 were significantly associated with breast cancer risk in different populations.
| S-EPMC4523945 | biostudies-literature
Project description:BackgroundA breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells.MethodsWe used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells.ResultsWe found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner.ConclusionsThese results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.
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Project description:It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study. Pearson's chi-square test or Fisher's exact test revealed that rs9933638, rs12443621, and rs3104746 were significantly associated with lung cancer risk (P < 0.001, P < 0.001, and P = 0.005, respectively). Logistic regression analyses displayed that lung cancer risk of individuals with rs9933638(GG+GA) were 1.89 times higher than that of rs9933638AA carriers (OR = 1.893, 95% CI = 1.308-2.741, P = 0.001). Similar findings were manifested for rs12443621 (OR = 1.824, 95% CI = 1.272-2.616, P = 0.001, rs12443621(GG+GA) carriers vs. rs12443621AA carriers) and rs3104746 (OR = 1.665, 95% CI = 1.243-2.230, P = 0.001, rs3104746TT carriers vs. rs3104746(TA+AA) carriers). The study discovered for the first time that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, providing new evidences that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent.
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Project description:PurposePhosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA-mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA-mutations in a cohort of early stage breast cancer patients and the association to the course of disease.Patients and methodsFrom an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA-mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA-mutations to recurrence-free interval (RFI) and overall survival.ResultsPIK3CA-mutation rate was 26.7% (300 of 1123). PIK3CA-mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired RFI was observed (adjusted HR 1.64, 95% CI 0.958-2.807), whilst in SHR-negative BCs PIK3CA-mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152-1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA-mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385-13.920), whilst no impact was observed in tamoxifen treated patients.ConclusionThis cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.
| S-EPMC9633529 | biostudies-literature
Project description:BackgroundIt is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.MethodsThe study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.ResultsWe detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P = 0.007).ConclusionsWithout prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.
| S-EPMC5863855 | biostudies-literature
Project description:We aimed to explore the effect of the breast cancer susceptibility gene TOX3 on estrogen synthesis from the perspective of estrogen production, in an attempt to link abnormalities in hormone production with the development of breast cancer. After overexpression of TOX3, several crucial key genes and pathways that contribute to estrogen production were upregulated. Forced expression of TOX3 also promotes proliferation and inhibits apoptosis of granulosa cells. These findings discuss the possible impact of susceptibility genes and steroid hormones on breast cancer from the perspective of extra-mammary tissues such as those in the ovary, thus providing new insights for early prevention and treatment of breast cancer.
2021-02-04 | GSE161341 | GEO