Carcinogenesis Advance Access originally published online on December 20, 2006
Carcinogenesis 2007 28(5):1067-1073; doi:10.1093/carcin/bgl250
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Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer
Center of Breast Diseases and Department of Abdominal Surgery
1 Department of Etiology and Carcinogenesis
2 Department of Pathology
3 Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
* To whom correspondence should be addressed. Tel: +86 1087788491; Fax: +86 1067722460; Email: dlin{at}public.bta.net.cn
The FAS–FASL system plays crucial role in counterattack of cancer cell against immune system. This study examined the effects of FAS (–1377G/A and –670A/G) and FASL (–844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case–control analysis of 840 patients and 840 controls. The effects on T-lymphocyte apoptosis were determined by activation-induced cell death (AICD) of T cells ex vivo and by analyzing apoptotic tumor-infiltrating lymphocytes (TILs) in breast cancer tissue. We found moderately increased risk associated with FAS –1377AG [odds ratio (OR), 1.29; 95% confidence interval (CI), 1.05–1.59] and –1377AA (OR, 1.36; 95% CI, 1.01–1.82) genotypes compared with the –1377GG genotype and decreased risk associated with FASL –844CT (OR, 0.76; 95% CI, 0.62–0.94) and –844TT (OR, 0.66; 95% CI, 0.43–1.00) genotypes compared with the –844CC genotype. T lymphocytes with the FASL –844CC genotype had heightened FASL expression that is associated with increased AICD of the T cells stimulated by MCF-7 cells or phytohemagglutinin compared with the FASL –844TT genotype (10.38 ± 4.09% and 24.29 ± 1.50% versus 6.03 ± 0.41% and 17.96 ± 3.66%; P < 0.05 and 0.001). Breast cancer patients with the FASL –844CC genotype had higher apoptotic TILs in their cancer tissues than those with the FASL –844TT genotype (33.7 ± 1.2% versus 19.1 ± 2.0%; P = 0.007). These findings indicate that functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.
Abbreviations: AICD, activation-induced cell death; CI, confidence interval; FASL, FAS ligand; MMC, mitomycin C; OR, odds ratio; PBMC, peripheral blood mononuclear cell; SNP, Single nucleotide polymorphism; TIL, tumor-infiltrating lymphocyte; TUNEL, transferase-mediated dUTP nick end labeling
These authors contributed equally to this work. Received October 17, 2006; revised November 14, 2006; accepted December 10, 2006.
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