FasL:Fas ratio--a prognostic factor in breast carcinomas.

Department of Obstetrics and Gynecology, University of Rostock, Germany.
Cancer Research (Impact Factor: 8.65). 02/2000; 60(4):822-8.
Source: PubMed

ABSTRACT Programmed cell death (apoptosis) is primarily mediated by Fas ligand (FasL; CD95L) and the Fas receptor (Fas; CD95). In this study, FasL was detected by immunohistochemical analysis in 85% of breast carcinomas and 14% of fibroadenomas randomly chosen, indicating that high expression of FasL might play a role in tumor pathology. FasL and Fas levels as well as FasL:Fas ratios were further ascertained in 215 human breast tumors, including 199 invasive ductal carcinomas, by real-time quantitative reverse transcription-PCR and compared with expression levels and ratios found in 25 normal human tissues, in 37 fibroadenomas, and in 5 normal breast tissues. Among breast carcinomas, high FasL mRNA expression seems to be positively correlated with histological grading (n = 212; P<0.0001). A ratio of FasL:Fas mRNA transcripts >1 is found to be significantly associated with decreased patient's disease-free survival (n = 211; P<0.03) and increased mortality (n = 211; P = 0.19). A FasL:Fas ratio >1 is related to tumor progression scored by histological grading (n = 212; P<0.02). The selection process leading to highly aggressive breast tumor variants might be enhanced by FasL-mediated tumor fratricide, eventually a possible target for novel therapeutic strategies.

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    ABSTRACT: FAS and FAS ligand (FASL) play crucial roles in apoptotic signaling, and deregulation of this pathway may facilitate carcinogenesis. Studies on the association between the FAS/FASL polymorphisms (FAS-1377G/A rs2234767, FAS-670A/G rs1800682, and FASL-844C/T rs763110) and breast cancer risk have reported inconsistent results. Therefore, to characterize the relationship between those polymorphisms and breast cancer risk, we undertook a meta-analysis of those studies. Several electronic databases were searched for articles on the FAS/FASL polymorphisms and breast cancer risk. The genotype data were extracted; pooled odds ratios (OR) with 95 % confidence intervals (CIs) were used to estimate the strength of the association. Five studies were eligible for our meta-analysis. Overall, we observed significant associations of the FAS-1377G/A polymorphism with breast cancer susceptibility (AG vs. GG: OR = 1.15, 95 % CI 1.02-1.30; AA vs. GG: OR = 1.39, 95 % CI 1.12-1.72; AG/AA vs. GG: OR = 1.18, 95 % CI, 1.16-1.32; A vs. G: OR = 1.16, 95 % CI 1.06-1.26), but we did not observe significant association of the Fas-670A/G and FasL-844C/T polymorphisms with breast cancer risk. In the subgroup analysis, we observed that the FAS-1377G/A and FASL-844C/T polymorphisms were associated with breast cancer risk in Chinese but not Whites; we still did not observed association of the FAS-670A/G polymorphism with breast cancer risk. Our meta-analysis revealed that FAS-1377G>A polymorphism was associated with an increased risk of breast cancer. FASL-844C>T polymorphism might be associated with a reduced breast cancer risk in Chinese. However, FAS-670A/G had no any effect on breast carcinogenesis.
    Tumor Biology 11/2013; · 2.52 Impact Factor
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    ABSTRACT: Accumulating evidences indicate that the functional FAS -1377G>A, -670A>G and FASL -844T>C polymorphisms affect the risk of several kinds of cancers. However, their roles in development of larynx and hypopharynx squamous cell carcinoma (SCC) were still unknown in Chinese. In the current study, we examined whether these functional genetic variants were associated with the risk of larynx and hypopharynx squamous SCC in a Han Chinese population. The FAS and FASL polymorphisms were genotyped in 300 patients with laryngeal and hypopharyngeal SCC and 300 control subjects by polymerase chain reactionerestriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis revealed that subjects carrying the FASL -844CT or TT genotype had a significantly decreased risk of developing laryngeal and hypopharyngeal SCC [odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.51-0.93; P = 0.016; or, OR = 0.41; 95% CI = 0.20-0.86; P = 0.009] compared with those carrying the CC genotype. Joint gene-smoking and gene-drinking effects were also observed, with the OR of CC genotype for smokers or drinkers were 5.15 (95%CI = 3.24-8.97) or 12.52 (95%CI = 7.31-22.47), respectively. Therefore, the FASL -844T>C polymorphism is associated with genetic susceptibility of developing laryngeal and hypopharyngeal SCC in a Han Chinese population.
    Gene 04/2013; · 2.20 Impact Factor
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    ABSTRACT: Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here we report that serum levels of CD95L are higher in TNBC patients compared to other breast cancer patients. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility, due to formation of an unconventional CD95-containing receptosome termed the motility-inducing signaling complex. Formation of this complex was instrumental for Nox3-driven ROS generation. Mechanistic investigations revealed a Yes-Orai1-EGFR-PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a pro-metastatic function for metalloprotease-cleaved CD95L in triple-negative breast cancers, revisiting its role in carcinogenesis.
    Cancer Research 09/2013; · 8.65 Impact Factor

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