研究TLR3及其介导通路在乳腺癌发生发展中的地位
|
摘要
Toll样受体(Toll like receptors, TLRs)家族是近年新发现一类信号通路基因,早先被认为是天然免疫模式识别的主要受体,并控制着由天然免疫向获得性免疫的转变。TLR信号通路并不是单一的直线传导,而是与多个信号通路之间存在着交联和融合,组成了复杂的信号网络。最近的研究显示,不仅外源性分子,许多内源性分子也能经TLRs信号传导途径激活免疫应答。其家族成员之一,Toll样受体3(TLR3)所介导的通路中有两个关键基因核转录因子kappaB (NF-kappaB)和B细胞编码k轻链多肽基因抑制激酶E(IKBKE)被证实与乳腺癌的进展密切相关,但对于该通路关键基因TLR3和IKBKE在乳腺癌发生中的研究尚处于空白。因此在第一部分研究中我们选取TLR3所介导的通路中的三个关键基因TLR3、IKBKE和Toll样受体接头分子1(TICAM1)作为乳腺癌易感候选基因,并选取三个基因中的17个SNP位点进行分型及关联分析。首先,我们通过一期病例对照研究(n=2,303例)发现三个TLR3基因多态与散发性乳腺癌显著相关。这三个位点为rs5743305、rs5743312、rs3775296,分别位于TLR3启动子区、内含子区和5’非翻译区(5'UTR)。其中’rLR3启动子区域SNP rs5743305的-926bpA等位基因能显著增加乳腺癌发生风险,OR为1.220(95%CI为1.059-1.407,P=0.007)；rs5743312的T等位基因型能显著增加乳腺癌的发生风险,OR为1.173(95%CI为1.046-1.315,P=0.006),rs3775296的+95T等位基因型能显著增加乳腺癌的发生风险,OR为1.159(95%CI为1.036-1.298,P=0.011)。这些一期研究中的发现,在第二期以家族性／早发性人群为主的病例对照研究中得到了进一步验证(n=l,248)。两期研究(n=3,551)的联合P值分别是1.97×10-4(rs5743305)、7.01×10-5(rs5743312)和8.69×10-5(rs3775296)。我们发现风险位点仅集中在TLR3基因中,进而我们研究了位于该基因启动子-926bp区域具有潜在功能意义的位点—rs5743305的作用机制。通过瞬时转录和荧光活性检测,我们在不同的细胞系里均观察到相似的趋势,即风险等位基因-926A相对于保护型等位基因-926T能够使转录降低活性30-50%。在MCF-7和MDA-MB-231细胞系中,这种差别具有统计学差异。第一部分的研究提示TLR3是一个乳腺癌易感基因,TLR3的基因多态性与乳腺癌的发生相关,其启动子区域的-926A>T多态的低转录活性等位基因(A-allele)与分子流行病学的风险型等位基因(A-allele)一致,提示TLR3高表达可能降低乳腺癌风险。
第一部分研究对TLR3介导的通路中的关键基因TLR3、IKBKE、TICAM1与乳腺癌的发生进行了关联分析及功能论证,初步揭示该通路中与乳腺癌发生的风险基因主要集中在TLR3基因上。通过对其启动子区域风险多态-926bpA>T的功能学研究发现,TLR3表达降低与乳腺癌风险增加相关。这向我们提示TLR3基因本身对乳腺癌的发生发展具有一定的影响。目前TLR3的研究多数集中在TLR3信号参与的肿瘤免疫调节,主要通过MyD88-IRAK-TRAF6-NF-kappaB途径影响免疫相关基因的表达,发挥抗肿瘤作用。近期越来越多的研究发现TLR3在肿瘤发生的不同阶段、不同肿瘤甚至相同肿瘤不同细胞系中发挥不同的作用。关于TLR3在乳腺癌中的地位的研究几近空白,因此有理由对TLR3基因在乳腺癌中的地位及可能的作用机制进行进一步研究。该部分中,我们构建了TLR3表达质粒,建立人乳腺癌TLR3稳定转染细胞株,通过体内、体外实验研究观察TLR3对人乳腺癌细胞增殖、侵袭、转移等生物学行为的影响。并在临床标本中观察TLR3基因的表达对生物学表型的影响。体外实验结果显示：TLR3稳定高表达的细胞出现明显的增殖抑制；细胞S期比例降低,细胞发生G1期阻滞；运动与侵袭能力减弱。体内实验得到了进一步证明：高表达TLR3基因细胞的移植瘤成瘤的时间晚于对照组,生长速度和肿瘤体积明显减小。进一步对机制的研究发现：TLR3的高表达可通过Caspase家族和Bcl-2家族共同调控促进凋亡,并抑制EGFR/PI3K/AKT通路活性。最后,我们在组织标本中证实正常乳腺组织中比癌组织中TLR3表达水平更高。总之,我们的研究提示TLR3至少通过抑制EGFR/PI3K/AKT增殖通路及激活凋亡途径,遏制乳腺癌的进展。
Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLRs play a crucial role in defending against pathogenic microbial infection through the induction of inflammatory cytokines and typeⅠinterferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. Two key factors in TLR3 pathway, NF-kappaB and IKBKE have been reported to have tight relationship with the progression of breast cancer. However, no research has been done to analysis the function of TLR3 and IKBKE on breast cancer development. Therefore, seventeen SNP points in three genes, TLR3, IKBKE and TICAM1, were selected to address the association between polymorphisms withinTLR3 and breast cancer. We performed case-control studies to investigate the contributions of genetic variants/haplotypes of the TLR3 gene to breast cancer risk. In the first hospital-based study (n=2,303), we observed significant associations between the incidence of breast cancer and rs5743305, rs5743312, and rs3775296 polymorphism. Increased risk was associated with the D-allele of-926A (odds ratio (OR),1.220; P=0.0007) and the rs5743312 T (OR,1.173; P=0.006). The associations were successfully replicated in an independent population set (familial/early-onset breast cancer cases and community-based controls, n=1,248). The combined P-values of the two studies (n=3,551) are 1.97×10-4 (rs5743305), 7.01×10-5 (rs5743312) and 8.69×10-5 (rs3775296). Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele,-926A>T-allele of rs5743305. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of TLR3 mRNA than those in normal breast tissues harboring risk genotypes. Taken together, the data presented here strongly suggest that TLR3 is a susceptibility gene for breast carcinogenesis.
We have shown that TLR3 is a susceptibility gene for breast carcinogenesis. Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele,-926A>T-allele of rs5743305. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of TLR3 mRNA than those in normal breast tissues harboring risk genotypes. Human TLR3 cDNA was reintroduced into the breast cancer cells by stable transfection. Effects of TLR3 on the proliferation and invasion of the cells were investigated by MTT, flow cytometry and transwell. Human breast cancer cells were implanted orthotopically into mice. Expression of Bcl-2 and Caspase were detected by Western blot. The results show that human TLR3 cDNA was reintroduced into the breast cancer cells. We demonstrated that TLR3 over-expression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with Bcl-2 protein levels and through inhibition of EGFR/PI3K/AKT pathway. In breast cancer samples, we also demonstrated that higher level of the TLR3 mRNA. TLR3 is a negative regulator of growth in breast cancer, mainly by inhibition of EGFR/PI3K/AKT proliferation pathway and activation of apoptosis.
第一部分研究对TLR3介导的通路中的关键基因TLR3、IKBKE、TICAM1与乳腺癌的发生进行了关联分析及功能论证,初步揭示该通路中与乳腺癌发生的风险基因主要集中在TLR3基因上。通过对其启动子区域风险多态-926bpA>T的功能学研究发现,TLR3表达降低与乳腺癌风险增加相关。这向我们提示TLR3基因本身对乳腺癌的发生发展具有一定的影响。目前TLR3的研究多数集中在TLR3信号参与的肿瘤免疫调节,主要通过MyD88-IRAK-TRAF6-NF-kappaB途径影响免疫相关基因的表达,发挥抗肿瘤作用。近期越来越多的研究发现TLR3在肿瘤发生的不同阶段、不同肿瘤甚至相同肿瘤不同细胞系中发挥不同的作用。关于TLR3在乳腺癌中的地位的研究几近空白,因此有理由对TLR3基因在乳腺癌中的地位及可能的作用机制进行进一步研究。该部分中,我们构建了TLR3表达质粒,建立人乳腺癌TLR3稳定转染细胞株,通过体内、体外实验研究观察TLR3对人乳腺癌细胞增殖、侵袭、转移等生物学行为的影响。并在临床标本中观察TLR3基因的表达对生物学表型的影响。体外实验结果显示：TLR3稳定高表达的细胞出现明显的增殖抑制；细胞S期比例降低,细胞发生G1期阻滞；运动与侵袭能力减弱。体内实验得到了进一步证明：高表达TLR3基因细胞的移植瘤成瘤的时间晚于对照组,生长速度和肿瘤体积明显减小。进一步对机制的研究发现：TLR3的高表达可通过Caspase家族和Bcl-2家族共同调控促进凋亡,并抑制EGFR/PI3K/AKT通路活性。最后,我们在组织标本中证实正常乳腺组织中比癌组织中TLR3表达水平更高。总之,我们的研究提示TLR3至少通过抑制EGFR/PI3K/AKT增殖通路及激活凋亡途径,遏制乳腺癌的进展。
Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. TLRs play a crucial role in defending against pathogenic microbial infection through the induction of inflammatory cytokines and typeⅠinterferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. Two key factors in TLR3 pathway, NF-kappaB and IKBKE have been reported to have tight relationship with the progression of breast cancer. However, no research has been done to analysis the function of TLR3 and IKBKE on breast cancer development. Therefore, seventeen SNP points in three genes, TLR3, IKBKE and TICAM1, were selected to address the association between polymorphisms withinTLR3 and breast cancer. We performed case-control studies to investigate the contributions of genetic variants/haplotypes of the TLR3 gene to breast cancer risk. In the first hospital-based study (n=2,303), we observed significant associations between the incidence of breast cancer and rs5743305, rs5743312, and rs3775296 polymorphism. Increased risk was associated with the D-allele of-926A (odds ratio (OR),1.220; P=0.0007) and the rs5743312 T (OR,1.173; P=0.006). The associations were successfully replicated in an independent population set (familial/early-onset breast cancer cases and community-based controls, n=1,248). The combined P-values of the two studies (n=3,551) are 1.97×10-4 (rs5743305), 7.01×10-5 (rs5743312) and 8.69×10-5 (rs3775296). Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele,-926A>T-allele of rs5743305. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of TLR3 mRNA than those in normal breast tissues harboring risk genotypes. Taken together, the data presented here strongly suggest that TLR3 is a susceptibility gene for breast carcinogenesis.
We have shown that TLR3 is a susceptibility gene for breast carcinogenesis. Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele,-926A>T-allele of rs5743305. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of TLR3 mRNA than those in normal breast tissues harboring risk genotypes. Human TLR3 cDNA was reintroduced into the breast cancer cells by stable transfection. Effects of TLR3 on the proliferation and invasion of the cells were investigated by MTT, flow cytometry and transwell. Human breast cancer cells were implanted orthotopically into mice. Expression of Bcl-2 and Caspase were detected by Western blot. The results show that human TLR3 cDNA was reintroduced into the breast cancer cells. We demonstrated that TLR3 over-expression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with Bcl-2 protein levels and through inhibition of EGFR/PI3K/AKT pathway. In breast cancer samples, we also demonstrated that higher level of the TLR3 mRNA. TLR3 is a negative regulator of growth in breast cancer, mainly by inhibition of EGFR/PI3K/AKT proliferation pathway and activation of apoptosis.
引文
1. Jemal, A., et al., Cancer statistics,2006. CA Cancer J Clin,2006.56(2):p. 106-30.
2. Fan, L., et al., Breast cancer in a transitional society over 18 years:trends and present status in Shanghai, China. Breast Cancer Res Treat,2009.117(2):p. 409-16.
3. Yu, K.D., et al., Development and trends of surgical modalities for breast cancer in China:a review of 16-year data. Ann Surg Oncol,2007.14(9):p. 2502-9.
4. Walsh, T. and M.C. King, Ten genes for inherited breast cancer. Cancer Cell, 2007.11(2):p.103-5.
5. De Vivo, I., et al., A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A,2002.99(19):p.12263-8.
6. Levy-Lahad, E., et al., A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCAl carriers. Proc Natl Acad Sci U S A,2001.98(6):p.3232-6.
7. Wolff, T.A. and J.E. Wilson, Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Am Fam Physician,2006. 74(10):p.1759-60.
8. Nelson, H.D., et al., Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility:systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med,2005.143(5):p.362-79.
9. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
10. Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature,2007.447(7148):p.1087-93.
11. Risbridger, G.P., et al., Breast and prostate cancer:more similar than different. Nat Rev Cancer.10(3):p.205-12.
12. Soengas, M.S., Cancer:Ins and outs of tumour control. Nature,2008. 454(7204):p.586-7.
13. Alatise, O.I. and G.N. Schrauzer, Lead Exposure:A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women. Biol Trace Elem Res.
14. Fujimoto, H., et al., Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer,2009.125(6):p.1276-84.
15. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
16. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
17. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
18. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
19. Eddy, S.F., et al., Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res,2005.65(24):p.11375-83.
20. Nehra, R., et al., BCL2 and CASP8 regulation by NF-{kappa}B differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and-resistant breast cancer cells. FASEB J.
21. Frasor, J., et al., Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res,2009.69(23):p.8918-25.
22. Guo, J.P., et al., Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol,2009. 175(1):p.324-33.
23. Boehm, J.S., et al., Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell,2007.129(6):p.1065-79.
24. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
25. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
26. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
27. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
28. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
29. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type Ⅰ Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
30. Ames, B.N., Cancer prevention and diet:help from single nucleotide polymorphisms. Proc Natl Acad Sci U S A,1999.96(22):p.12216-8.
1. Risbridger, G.P., et al., Breast and prostate cancer:more similar than different. Nat Rev Cancer.10(3):p.205-12.
2. Soengas, M.S., Cancer:Ins and outs of tumour control. Nature,2008. 454(7204):p.586-7.
3. Alatise, O.I. and G.N. Schrauzer, Lead Exposure:A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women. Biol Trace Elem Res.
4. Fujimoto, H., et al., Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer,2009.125(6):p.1276-84.
5. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
6. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
7. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
8. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
9. Eddy, S.F., et al., Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res,2005.65(24):p.11375-83.
10. Nehra, R., et al., BCL2 and CASP8 regulation by NF-{kappa}B differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and-resistant breast cancer cells. FASEB J.
11. Frasor, J., et al., Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res,2009.69(23):p.8918-25.
12. Guo, J.P., et al., Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol,2009. 175(1):p.324-33.
13. Boehm, J.S., et al., Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell,2007.129(6):p.1065-79.
14. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
15. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
16. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
17. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
18. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
19. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
20. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
21. Etokebe, G.E., et al., Single-nucleotide polymorphisms in genes encoding toll-like receptor-2,-3,-4, and-9 in case-control study with breast cancer. Genet Test Mol Biomarkers,2009.13(6):p.729-34.
22. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
23. Song, C.G., et al., The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer. J Cancer Res Clin Oncol,2006.132(10):p. 617-26.
24. Cao, A.Y., et al., Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat,2009.115(1):p.51-5.
25. Cao, A.Y., et al., The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat,2009.114(3):p.457-62.
26. Yu, K.D., et al., Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1. Breast Cancer Res Treat,2009.
27. Yu, K.D., et al., Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet,2009.18(13):p.2502-17.
28. Ahmad, A., et al., Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem,2009.108(4):p.916-25.
29. Bell, P.A., et al., SNPstream UHT:ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques,2002. Suppl:p.70-2, 74,76-7.
30. Morimoto, Y., et al., Single nucleotide polymorphism in fibroblast growth factor receptor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma. Cancer,2003.98(10):p.2245-50.
31. Orphanos, V., et al., Proximal 6q, a region showing allele loss in primary breast cancer. Br J Cancer,1995.71(2):p.290-3.
32. Tang, J., et al., Genotyping TAP2 variants in North American Caucasians, Brazilians, and Africans. Genes Immun,2001.2(1):p.32-40.
33. Moshynska, O., et al., G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression. Oncogene,2005.24(12):p.2042-9.
34. Mitchell, P.J., C. Wang, and R. Tjian, Positive and negative regulation of transcription in vitro:enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell,1987.50(6):p.847-61.
35. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res,2001.29(9):p. e45.
36. Walsh, T. and M.C. King, Ten genes for inherited breast cancer. Cancer Cell, 2007.11(2):p.103-5.
37. Johnson, N., et al., Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet,2007.16(9):p. 1051-7.
38. Chen, P., et al., Association of common PALB2 polymorphisms with breast cancer risk:a case-control study. Clin Cancer Res,2008.14(18):p.5931-7.
39. Song, H., et al., Tagging single nucleotide polymorphisms in the BRIP1 gene and susceptibility to breast and ovarian cancer. PLoS One,2007.2(3):p. e268.
40. Peto, J., Breast cancer susceptibility-A new look at an old model. Cancer Cell, 2002.1(5):p.411-2.
41. Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature,2007.447(7148):p.1087-93.
42. Easton, D.F. and R.A. Eeles, Genome-wide association studies in cancer. Hum Mol Genet,2008.17(R2):p. R109-15.
1. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
2. Weber, A., et al., Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ,2009.
3. Wu, J., et al., Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology,2009.
4. Telepnev, M.V., et al., Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor-mediated signaling pathways in human dendritic cells. J Infect Dis,2009.200(11):p.1694-702.
5. Smith, K.A., et al., Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. Clin Cancer Res,2009.15(19):p. 6167-76.
6. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
7. Dohnal, A.M., et al., CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med,2009.13(8B):p.1741-50.
8. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
9. Adams, M., et al., The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine,2005.23(17-18):p.2374-8.
10. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
11. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
12. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res,2001.29(9):p. e45.
13. Chattopadhyay, R., A. Bhattacharyya, and S.E. Crowe, Dual regulation by apurinic/apyrimidinic endonuclease-1 inhibits gastric epithelial cell apoptosis during Helicobacter pylori infection. Cancer Res.70(7):p.2799-808.
14. Borralho, P.M., et al., MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells. FEBS J, 2009.276(22):p.6689-700.
15. Yu, K.D., et al., Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet,2009.18(13):p.2502-17.
16. Cowie, R.V., et al., Acute behavioral effects of intrapleural OK-432 (Picibanil) administration in preterm fetal sheep. Fetal Diagn Ther,2009.25(3):p. 304-13.
17. Oshikawa, T., et al., Antitumor effect of OK-432-derived DNA:one of the active constituents of OK-432, a streptococcal immunotherapeutic agent. J Immunother,2006.29(2):p.143-50.
18. Bratton, S.B., et al., Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res,2000.256(1):p. 27-33.
19. Burri, S.H., et al.,'Loop'domain deletional mutant of Bcl-xL is as effective as p29Bcl-xL in inhibiting radiation-induced cytosolic accumulation of cytochrome c (cyt c), caspase-3 activity, and apoptosis. Int J Radiat Oncol Biol Phys,1999.43(2):p.423-30.
20. Mandal, M., et al., Bcl-2 prevents CD95 (Fas/APO-1)-induced degradation of lamin B and poly(ADP-ribose) polymerase and restores the NF-kappaB signaling pathway.J Biol Chem,1996.271(48):p.30354-9.
21. van de Wetering, D., et al., Salmonella induced IL-23 and IL-1 beta allow for IL-12 production by monocytes and Mphil through induction of IFN-gamma in CD56 NK/NK-like T cells. PLoS One,2009.4(12):p. e8396.
22. Furukawa, T., M. Sunamura, and A. Horii, Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci,2006.97(1):p.1-7.
23. Kuramitsu, Y. and K. Nakamura, Proteomic analysis of cancer tissues: shedding light on carcinogenesis and possible biomarkers. Proteomics,2006. 6(20):p.5650-61.
24. Petersen, M., et al., Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene. 29(9):p.1351-61.
25. Gentner, B., et al., Differences in the gene expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in primary colorectal tumors and their synchronous liver metastases. Anticancer Res,2009.29(1):p. 67-74.
26. Dong, P., et al., Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Mol Cancer,2009.8:p.103.
27. Cappuzzo, F., et al., Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst,2004.96(15):p. 1133-41.
28. Milde-Langosch, K., et al., Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer,2005. 92(12):p.2206-15.
29. Shin, E., et al., Expression of down stream molecules of RET (p-ERK, p-p38 MAPK, p-JNK and p-AKT) in papillary thyroid carcinomas. Yonsei Med J, 2004.45(2):p.306-13.
30. Li, X.F., P.J. Yan, and Z.M. Shao, Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene,2009.28(44):p. 3937-48.
31. Chen, H., et al., Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression. Br J Cancer,2009.101(3):p.432-40.
32. Wozniak, B., et al., The effect of combined therapy on activity of cathepsin D and alpha-1-antitrypsin in the blood serum of women with cervical cancer. Eur J Gynaecol Oncol,2008.29(6):p.617-9.
33. Uenishi, Y., et al., Isolation and identification of arabinose mycolates of Cell Wall Skeleton (CWS) derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105). J Microbiol Methods,2010.80(3):p.302-5.
1. Rock, F.L., et al., A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A,1998.95(2):p.588-93.
2. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
3. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
4. Toma, C., et al., Pathogenic Vibrio Activate NLRP3 Inflammasome via Cytotoxins and TLR/Nucleotide-Binding Oligomerization Domain-Mediated NF-{kappa}B Signaling. J Immunol,2010.
5. Nguyen, T.T., et al., Differential gene expression downstream of Toll-like receptors (TLRs):Role of c-Src and activating transcription factor 3 (ATF3). J Biol Chem,2010.
6. Park, S.J. and H.S. Youn, Isoliquiritigenin Suppresses the Toll-Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-beta (TRIF)-Dependent Signaling Pathway of Toll-Like Receptors by Targeting TBK1. J Agric Food Chem,2010.
7. Langlet, C., et al., PKC-alpha controls MYD88-dependent TLR/IL-1R signaling and cytokine production in mouse and human dendritic cells. Eur J Immunol,2010.40(2):p.505-15.
8. Shin, S.H. and Y.H. Lee, Airborne Fungi Induce Nasal Polyp Epithelial Cell Activation and Toll-Like Receptor Expression. Int Arch Allergy Immunol, 2010.153(1):p.46-52.
9. Fach, S.J., et al., Differential expression of cytokine transcripts in neonatal and adult ovine alveolar macrophages in response to respiratory syncytial virus or toll-like receptor ligation. Vet Immunol Immunopathol,2010.
10. Lin, Y.C., et al., Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway. Mol Immunol,2010.
11. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
12. Sadik, C.D., et al., Activation of interferon regulatory factor-3 via toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA. Nucleic Acids Res,2009.37(15):p. 5041-56.
13. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
14. Morikawa, T., et al., Identification of Toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clin Cancer Res,2007. 13(19):p.5703-9.
15. McCall, K.D., et al., High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology,2007.148(9):p.4226-37.
16. Radford, K.J., et al., CD11c+ blood dendritic cells induce antigen-specific cytotoxic T lymphocytes with similar efficiency compared to monocyte-derived dendritic cells despite higher levels of MHC class Ⅰ expression. J Immunother, 2006.29(6):p.596-605.
17. Fujita, H., et al., Langerhans cells exhibit low responsiveness to double-stranded RNA. Biochem Biophys Res Commun,2004.319(3):p. 832-9.
18. Maier, L.M., et al., NKG2D-RAE-1 receptor-ligand variation does not account for the NK cell defect in nonobese diabetic mice. J Immunol,2008.181(10):p. 7073-80.
19. Duluc, D., et al., PolyI:C plus IL-2 or IL-12 induce IFN-gamma production by human NK cells via autocrine IFN-beta. Eur J Immunol,2009.39(10):p. 2877-84.
20. Zhou, Y., et al., Activation of Toll-like receptors inhibits herpes simplex virus-1 infection of human neuronal cells. J Neurosci Res,2009.87(13):p.2916-25.
21. Ngoi, S.M., M.G. Tovey, and A.T. Vella, Targeting poly (I:C) to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFN-alpha/beta. J Immunol,2008.181(11):p.7670-80.
22. Bohnenkamp, H.R., et al., Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell type 1 responses. Cell Immunol,2007.247(2):p.72-84.
23. Tohyama, M., et al., dsRNA-mediated innate immunity of epidermal keratinocytes. Biochem Biophys Res Commun,2005.335(2):p.505-11.
24. Matsumoto, M. and T. Seya, TLR3:interferon induction by double-stranded RNA including poly (I:C). Adv Drug Deliv Rev,2008.60(7):p.805-12.
25. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
26. Jiang, G., et al., Regulatory role of TLR ligands on the activation of autoreactive T cells by retinal astrocytes. Invest Ophthalmol Vis Sci,2009. 50(10):p.4769-76.
27. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
28. Salaun, B., M. Greutert, and P. Romero, Toll-like receptor 3 is necessary for dsRNA adjuvant effects. Vaccine,2009.27(12):p.1841-7.
29. Liu, Y.C., et al., CpG-B oligodeoxynucleotides inhibit TLR-dependent and-independent induction of type Ⅰ IFN in dendritic cells. J Immunol,2010. 184(7):p.3367-76.
30. Cotter, C.R., et al., The virion host shut-off (vhs) protein blocks a TLR-independent pathway of herpes simplex virus type 1 recognition in human and mouse dendritic cells. PLoS One,2010.5(2):p. e8684.
31. Chen, S., et al., Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and-independent signaling and is reciprocally modulated by liver Ⅹ receptor activation. J Immunol,2008.181(10):p.7186-93.
32. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
33. Boonstra, A., et al., Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88-and TR1F-dependent TLR signals, and TLR-independent signals. J Immunol,2006. 177(11):p.7551-8.
34. Broad, A., J.A. Kirby, and D.E. Jones, Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology,2007.120(1):p. 103-11.
35. Delale, T., et al., MyD88-dependent and-independent murine cytomegalovirus sensing for IFN-alpha release and initiation of immune responses in vivo. J Immunol,2005.175(10):p.6723-32.
36. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
37. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
38. Adams, M., et al., The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine,2005.23(17-18):p.2374-8.
39. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
40. Weber, A., et al., Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ,2009.
41. Wu, J., et al., Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology,2009.
42. Telepnev, M.V., et al., Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor-mediated signaling pathways in human dendritic cells. J Infect Dis,2009.200(11):p.1694-702.
43. Smith, K.A., et al., Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. Clin Cancer Res,2009.15(19):p. 6167-76.
44. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
45. Dohnal, A.M., et al., CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med,2009.13(8B):p.1741-50.
46. Uenishi, Y., et al., Isolation and identification of arabinose mycolates of Cell Wall Skeleton (CWS) derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105). J Microbiol Methods,2010.80(3):p.302-5.
47. Cowie, R.V., et al., Acute behavioral effects of intrapleural OK-432 (Picibanil) administration in preterm fetal sheep. Fetal Diagn Ther,2009.25(3):p. 304-13.
48. Oshikawa, T., et al., Antitumor effect of OK-432-derived DNA:one of the active constituents of OK-432, a streptococcal immunotherapeutic agent. J Immunother,2006.29(2):p.143-50.
49. Clark, D.A., et al., Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model. I. Synergistic effect of LPS and (TNF-alpha+IFN-gamma) on pregnancy loss. Am J Reprod Immunol,2004.52(6):p.370-8.
50. Baba, N., et al., Selected commensal-related bacteria and Toll-like receptor 3 agonist combinatorial codes synergistically induce interleukin-12 production by dendritic cells to trigger a T helper type 1 polarizing programme. Immunology,2009.128(1 Suppl):p. e523-31.
51. Pulko, V., et al., TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination. J Immunol,2009.183(6):p.3634-41.
52. Etokebe, G.E., et al., Single-nucleotide polymorphisms in genes encoding toll-like receptor -2,-3,-4, and -9 in case-control study with breast cancer. Genet Test Mol Biomarkers,2009.13(6):p.729-34.
2. Fan, L., et al., Breast cancer in a transitional society over 18 years:trends and present status in Shanghai, China. Breast Cancer Res Treat,2009.117(2):p. 409-16.
3. Yu, K.D., et al., Development and trends of surgical modalities for breast cancer in China:a review of 16-year data. Ann Surg Oncol,2007.14(9):p. 2502-9.
4. Walsh, T. and M.C. King, Ten genes for inherited breast cancer. Cancer Cell, 2007.11(2):p.103-5.
5. De Vivo, I., et al., A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A,2002.99(19):p.12263-8.
6. Levy-Lahad, E., et al., A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCAl carriers. Proc Natl Acad Sci U S A,2001.98(6):p.3232-6.
7. Wolff, T.A. and J.E. Wilson, Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Am Fam Physician,2006. 74(10):p.1759-60.
8. Nelson, H.D., et al., Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility:systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med,2005.143(5):p.362-79.
9. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
10. Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature,2007.447(7148):p.1087-93.
11. Risbridger, G.P., et al., Breast and prostate cancer:more similar than different. Nat Rev Cancer.10(3):p.205-12.
12. Soengas, M.S., Cancer:Ins and outs of tumour control. Nature,2008. 454(7204):p.586-7.
13. Alatise, O.I. and G.N. Schrauzer, Lead Exposure:A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women. Biol Trace Elem Res.
14. Fujimoto, H., et al., Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer,2009.125(6):p.1276-84.
15. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
16. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
17. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
18. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
19. Eddy, S.F., et al., Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res,2005.65(24):p.11375-83.
20. Nehra, R., et al., BCL2 and CASP8 regulation by NF-{kappa}B differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and-resistant breast cancer cells. FASEB J.
21. Frasor, J., et al., Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res,2009.69(23):p.8918-25.
22. Guo, J.P., et al., Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol,2009. 175(1):p.324-33.
23. Boehm, J.S., et al., Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell,2007.129(6):p.1065-79.
24. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
25. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
26. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
27. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
28. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
29. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type Ⅰ Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
30. Ames, B.N., Cancer prevention and diet:help from single nucleotide polymorphisms. Proc Natl Acad Sci U S A,1999.96(22):p.12216-8.
1. Risbridger, G.P., et al., Breast and prostate cancer:more similar than different. Nat Rev Cancer.10(3):p.205-12.
2. Soengas, M.S., Cancer:Ins and outs of tumour control. Nature,2008. 454(7204):p.586-7.
3. Alatise, O.I. and G.N. Schrauzer, Lead Exposure:A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women. Biol Trace Elem Res.
4. Fujimoto, H., et al., Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer,2009.125(6):p.1276-84.
5. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
6. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
7. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
8. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
9. Eddy, S.F., et al., Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res,2005.65(24):p.11375-83.
10. Nehra, R., et al., BCL2 and CASP8 regulation by NF-{kappa}B differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and-resistant breast cancer cells. FASEB J.
11. Frasor, J., et al., Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res,2009.69(23):p.8918-25.
12. Guo, J.P., et al., Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer. Am J Pathol,2009. 175(1):p.324-33.
13. Boehm, J.S., et al., Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell,2007.129(6):p.1065-79.
14. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
15. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
16. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
17. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
18. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
19. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
20. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
21. Etokebe, G.E., et al., Single-nucleotide polymorphisms in genes encoding toll-like receptor-2,-3,-4, and-9 in case-control study with breast cancer. Genet Test Mol Biomarkers,2009.13(6):p.729-34.
22. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
23. Song, C.G., et al., The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer. J Cancer Res Clin Oncol,2006.132(10):p. 617-26.
24. Cao, A.Y., et al., Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat,2009.115(1):p.51-5.
25. Cao, A.Y., et al., The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. Breast Cancer Res Treat,2009.114(3):p.457-62.
26. Yu, K.D., et al., Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1. Breast Cancer Res Treat,2009.
27. Yu, K.D., et al., Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet,2009.18(13):p.2502-17.
28. Ahmad, A., et al., Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem,2009.108(4):p.916-25.
29. Bell, P.A., et al., SNPstream UHT:ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques,2002. Suppl:p.70-2, 74,76-7.
30. Morimoto, Y., et al., Single nucleotide polymorphism in fibroblast growth factor receptor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma. Cancer,2003.98(10):p.2245-50.
31. Orphanos, V., et al., Proximal 6q, a region showing allele loss in primary breast cancer. Br J Cancer,1995.71(2):p.290-3.
32. Tang, J., et al., Genotyping TAP2 variants in North American Caucasians, Brazilians, and Africans. Genes Immun,2001.2(1):p.32-40.
33. Moshynska, O., et al., G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression. Oncogene,2005.24(12):p.2042-9.
34. Mitchell, P.J., C. Wang, and R. Tjian, Positive and negative regulation of transcription in vitro:enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell,1987.50(6):p.847-61.
35. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res,2001.29(9):p. e45.
36. Walsh, T. and M.C. King, Ten genes for inherited breast cancer. Cancer Cell, 2007.11(2):p.103-5.
37. Johnson, N., et al., Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet,2007.16(9):p. 1051-7.
38. Chen, P., et al., Association of common PALB2 polymorphisms with breast cancer risk:a case-control study. Clin Cancer Res,2008.14(18):p.5931-7.
39. Song, H., et al., Tagging single nucleotide polymorphisms in the BRIP1 gene and susceptibility to breast and ovarian cancer. PLoS One,2007.2(3):p. e268.
40. Peto, J., Breast cancer susceptibility-A new look at an old model. Cancer Cell, 2002.1(5):p.411-2.
41. Easton, D.F., et al., Genome-wide association study identifies novel breast cancer susceptibility loci. Nature,2007.447(7148):p.1087-93.
42. Easton, D.F. and R.A. Eeles, Genome-wide association studies in cancer. Hum Mol Genet,2008.17(R2):p. R109-15.
1. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
2. Weber, A., et al., Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ,2009.
3. Wu, J., et al., Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology,2009.
4. Telepnev, M.V., et al., Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor-mediated signaling pathways in human dendritic cells. J Infect Dis,2009.200(11):p.1694-702.
5. Smith, K.A., et al., Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. Clin Cancer Res,2009.15(19):p. 6167-76.
6. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
7. Dohnal, A.M., et al., CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med,2009.13(8B):p.1741-50.
8. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
9. Adams, M., et al., The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine,2005.23(17-18):p.2374-8.
10. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
11. Li, W.F., et al., The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality:two recurrent mutations were identified. Breast Cancer Res Treat,2008.110(1):p.99-109.
12. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res,2001.29(9):p. e45.
13. Chattopadhyay, R., A. Bhattacharyya, and S.E. Crowe, Dual regulation by apurinic/apyrimidinic endonuclease-1 inhibits gastric epithelial cell apoptosis during Helicobacter pylori infection. Cancer Res.70(7):p.2799-808.
14. Borralho, P.M., et al., MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells. FEBS J, 2009.276(22):p.6689-700.
15. Yu, K.D., et al., Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet,2009.18(13):p.2502-17.
16. Cowie, R.V., et al., Acute behavioral effects of intrapleural OK-432 (Picibanil) administration in preterm fetal sheep. Fetal Diagn Ther,2009.25(3):p. 304-13.
17. Oshikawa, T., et al., Antitumor effect of OK-432-derived DNA:one of the active constituents of OK-432, a streptococcal immunotherapeutic agent. J Immunother,2006.29(2):p.143-50.
18. Bratton, S.B., et al., Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res,2000.256(1):p. 27-33.
19. Burri, S.H., et al.,'Loop'domain deletional mutant of Bcl-xL is as effective as p29Bcl-xL in inhibiting radiation-induced cytosolic accumulation of cytochrome c (cyt c), caspase-3 activity, and apoptosis. Int J Radiat Oncol Biol Phys,1999.43(2):p.423-30.
20. Mandal, M., et al., Bcl-2 prevents CD95 (Fas/APO-1)-induced degradation of lamin B and poly(ADP-ribose) polymerase and restores the NF-kappaB signaling pathway.J Biol Chem,1996.271(48):p.30354-9.
21. van de Wetering, D., et al., Salmonella induced IL-23 and IL-1 beta allow for IL-12 production by monocytes and Mphil through induction of IFN-gamma in CD56 NK/NK-like T cells. PLoS One,2009.4(12):p. e8396.
22. Furukawa, T., M. Sunamura, and A. Horii, Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci,2006.97(1):p.1-7.
23. Kuramitsu, Y. and K. Nakamura, Proteomic analysis of cancer tissues: shedding light on carcinogenesis and possible biomarkers. Proteomics,2006. 6(20):p.5650-61.
24. Petersen, M., et al., Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene. 29(9):p.1351-61.
25. Gentner, B., et al., Differences in the gene expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in primary colorectal tumors and their synchronous liver metastases. Anticancer Res,2009.29(1):p. 67-74.
26. Dong, P., et al., Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Mol Cancer,2009.8:p.103.
27. Cappuzzo, F., et al., Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst,2004.96(15):p. 1133-41.
28. Milde-Langosch, K., et al., Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer,2005. 92(12):p.2206-15.
29. Shin, E., et al., Expression of down stream molecules of RET (p-ERK, p-p38 MAPK, p-JNK and p-AKT) in papillary thyroid carcinomas. Yonsei Med J, 2004.45(2):p.306-13.
30. Li, X.F., P.J. Yan, and Z.M. Shao, Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene,2009.28(44):p. 3937-48.
31. Chen, H., et al., Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression. Br J Cancer,2009.101(3):p.432-40.
32. Wozniak, B., et al., The effect of combined therapy on activity of cathepsin D and alpha-1-antitrypsin in the blood serum of women with cervical cancer. Eur J Gynaecol Oncol,2008.29(6):p.617-9.
33. Uenishi, Y., et al., Isolation and identification of arabinose mycolates of Cell Wall Skeleton (CWS) derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105). J Microbiol Methods,2010.80(3):p.302-5.
1. Rock, F.L., et al., A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci U S A,1998.95(2):p.588-93.
2. Takeda, K. and S. Akira, Toll-like receptors. Curr Protoc Immunol,2007. Chapter 14:p. Unit 14 12.
3. Sonnex, C., Toll-like receptors and genital tract infection. Int J STD AIDS, 2010.21(3):p.153-7.
4. Toma, C., et al., Pathogenic Vibrio Activate NLRP3 Inflammasome via Cytotoxins and TLR/Nucleotide-Binding Oligomerization Domain-Mediated NF-{kappa}B Signaling. J Immunol,2010.
5. Nguyen, T.T., et al., Differential gene expression downstream of Toll-like receptors (TLRs):Role of c-Src and activating transcription factor 3 (ATF3). J Biol Chem,2010.
6. Park, S.J. and H.S. Youn, Isoliquiritigenin Suppresses the Toll-Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-beta (TRIF)-Dependent Signaling Pathway of Toll-Like Receptors by Targeting TBK1. J Agric Food Chem,2010.
7. Langlet, C., et al., PKC-alpha controls MYD88-dependent TLR/IL-1R signaling and cytokine production in mouse and human dendritic cells. Eur J Immunol,2010.40(2):p.505-15.
8. Shin, S.H. and Y.H. Lee, Airborne Fungi Induce Nasal Polyp Epithelial Cell Activation and Toll-Like Receptor Expression. Int Arch Allergy Immunol, 2010.153(1):p.46-52.
9. Fach, S.J., et al., Differential expression of cytokine transcripts in neonatal and adult ovine alveolar macrophages in response to respiratory syncytial virus or toll-like receptor ligation. Vet Immunol Immunopathol,2010.
10. Lin, Y.C., et al., Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway. Mol Immunol,2010.
11. Peng, J., et al., SARM inhibits both TRIF-and MyD88-mediated AP-1 activation. Eur J Immunol,2010.
12. Sadik, C.D., et al., Activation of interferon regulatory factor-3 via toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA. Nucleic Acids Res,2009.37(15):p. 5041-56.
13. Andrade, C.F., et al., Toll-like receptor and cytokine gene expression in the early phase of human lung transplantation. J Heart Lung Transplant,2006. 25(11):p.1317-23.
14. Morikawa, T., et al., Identification of Toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clin Cancer Res,2007. 13(19):p.5703-9.
15. McCall, K.D., et al., High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology,2007.148(9):p.4226-37.
16. Radford, K.J., et al., CD11c+ blood dendritic cells induce antigen-specific cytotoxic T lymphocytes with similar efficiency compared to monocyte-derived dendritic cells despite higher levels of MHC class Ⅰ expression. J Immunother, 2006.29(6):p.596-605.
17. Fujita, H., et al., Langerhans cells exhibit low responsiveness to double-stranded RNA. Biochem Biophys Res Commun,2004.319(3):p. 832-9.
18. Maier, L.M., et al., NKG2D-RAE-1 receptor-ligand variation does not account for the NK cell defect in nonobese diabetic mice. J Immunol,2008.181(10):p. 7073-80.
19. Duluc, D., et al., PolyI:C plus IL-2 or IL-12 induce IFN-gamma production by human NK cells via autocrine IFN-beta. Eur J Immunol,2009.39(10):p. 2877-84.
20. Zhou, Y., et al., Activation of Toll-like receptors inhibits herpes simplex virus-1 infection of human neuronal cells. J Neurosci Res,2009.87(13):p.2916-25.
21. Ngoi, S.M., M.G. Tovey, and A.T. Vella, Targeting poly (I:C) to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFN-alpha/beta. J Immunol,2008.181(11):p.7670-80.
22. Bohnenkamp, H.R., et al., Synergism of Toll-like receptor-induced interleukin-12p70 secretion by monocyte-derived dendritic cells is mediated through p38 MAPK and lowers the threshold of T-helper cell type 1 responses. Cell Immunol,2007.247(2):p.72-84.
23. Tohyama, M., et al., dsRNA-mediated innate immunity of epidermal keratinocytes. Biochem Biophys Res Commun,2005.335(2):p.505-11.
24. Matsumoto, M. and T. Seya, TLR3:interferon induction by double-stranded RNA including poly (I:C). Adv Drug Deliv Rev,2008.60(7):p.805-12.
25. Alexopoulou, L., et al., Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature,2001.413(6857):p.732-8.
26. Jiang, G., et al., Regulatory role of TLR ligands on the activation of autoreactive T cells by retinal astrocytes. Invest Ophthalmol Vis Sci,2009. 50(10):p.4769-76.
27. Salaun, B., et al., TLR3 can directly trigger apoptosis in human cancer cells. J Immunol,2006.176(8):p.4894-901.
28. Salaun, B., M. Greutert, and P. Romero, Toll-like receptor 3 is necessary for dsRNA adjuvant effects. Vaccine,2009.27(12):p.1841-7.
29. Liu, Y.C., et al., CpG-B oligodeoxynucleotides inhibit TLR-dependent and-independent induction of type Ⅰ IFN in dendritic cells. J Immunol,2010. 184(7):p.3367-76.
30. Cotter, C.R., et al., The virion host shut-off (vhs) protein blocks a TLR-independent pathway of herpes simplex virus type 1 recognition in human and mouse dendritic cells. PLoS One,2010.5(2):p. e8684.
31. Chen, S., et al., Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and-independent signaling and is reciprocally modulated by liver Ⅹ receptor activation. J Immunol,2008.181(10):p.7186-93.
32. Abe, M., et al., Effects of statins on adipose tissue inflammation:their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol,2008.28(5):p.871-7.
33. Boonstra, A., et al., Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88-and TR1F-dependent TLR signals, and TLR-independent signals. J Immunol,2006. 177(11):p.7551-8.
34. Broad, A., J.A. Kirby, and D.E. Jones, Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology,2007.120(1):p. 103-11.
35. Delale, T., et al., MyD88-dependent and-independent murine cytomegalovirus sensing for IFN-alpha release and initiation of immune responses in vivo. J Immunol,2005.175(10):p.6723-32.
36. Rothenfusser, S., et al., The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol,2005. 175(8):p.5260-8.
37. Paone, A., et al., Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis, 2008.29(7):p.1334-42.
38. Adams, M., et al., The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine,2005.23(17-18):p.2374-8.
39. Wang, N., et al., Viral induction of the zinc finger antiviral protein is IRF3-dependent but NF-kappaB-independent. J Biol Chem,2010.285(9):p. 6080-90.
40. Weber, A., et al., Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ,2009.
41. Wu, J., et al., Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology,2009.
42. Telepnev, M.V., et al., Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor-mediated signaling pathways in human dendritic cells. J Infect Dis,2009.200(11):p.1694-702.
43. Smith, K.A., et al., Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. Clin Cancer Res,2009.15(19):p. 6167-76.
44. Chin, A.I., et al., Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance. Cancer Res,2010.70(7):p.2595-603.
45. Dohnal, A.M., et al., CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med,2009.13(8B):p.1741-50.
46. Uenishi, Y., et al., Isolation and identification of arabinose mycolates of Cell Wall Skeleton (CWS) derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105). J Microbiol Methods,2010.80(3):p.302-5.
47. Cowie, R.V., et al., Acute behavioral effects of intrapleural OK-432 (Picibanil) administration in preterm fetal sheep. Fetal Diagn Ther,2009.25(3):p. 304-13.
48. Oshikawa, T., et al., Antitumor effect of OK-432-derived DNA:one of the active constituents of OK-432, a streptococcal immunotherapeutic agent. J Immunother,2006.29(2):p.143-50.
49. Clark, D.A., et al., Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model. I. Synergistic effect of LPS and (TNF-alpha+IFN-gamma) on pregnancy loss. Am J Reprod Immunol,2004.52(6):p.370-8.
50. Baba, N., et al., Selected commensal-related bacteria and Toll-like receptor 3 agonist combinatorial codes synergistically induce interleukin-12 production by dendritic cells to trigger a T helper type 1 polarizing programme. Immunology,2009.128(1 Suppl):p. e523-31.
51. Pulko, V., et al., TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination. J Immunol,2009.183(6):p.3634-41.
52. Etokebe, G.E., et al., Single-nucleotide polymorphisms in genes encoding toll-like receptor -2,-3,-4, and -9 in case-control study with breast cancer. Genet Test Mol Biomarkers,2009.13(6):p.729-34.