Toll-Like Receptor-9 Expression Is Inversely Correlated with Estrogen Receptor Status in Breast Cancer

Jukkola-Vuorinen, Arja; Rahko, Eeva; Vuopala, Katri; Desmond, Reneé A.; Lehenkari, Petri; Harris, Kevin W.; Selander, Katri S.

doi:10.1159/000151602

Cited by 49 publications

(78 citation statements)

References 63 publications

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“…Interestingly, we also found that TLR9 expression was significantly higher in ER negative breast cancer compared with ER positive one in this study, which is consistent with the report by Jukkola-Vuorinen [16]. Given that TLR9 ligation could inhibit ERα-induced transactivation by activating NF-κB of breast cancer cells [11], we speculate that TLR9 may play a role in the transformation of breast cancer from hormone-dependent to hormone-independent stage.…”

Section: Discussionsupporting

confidence: 92%

“…However, we didn't observed a statistically significant difference concerning overall survival (OS) between TLR9 positive and negative breast cancer patients, which might be correlated with the limited interval from surgery and observation end point, but we did note that the longer we follow up, the wider was the difference between the two group of patients. In a recent study about the association of TLR9 and estrogen receptor expression, Jukkola-Vuorinen reported that distant metastasis-free survival was higher in the lower TLR9-expressing part of the cohort than in the higher TLR9-expressing part of breast cancer patients, which, together with our data suggested that TLR9 may be correlated with a poor prognosis by promoting metastasis of breast cancer (16). We will continue to follow those patients and analyze prospectively the association between clinical outcome of patients and TLR9 expression.…”

Section: Discussionsupporting

confidence: 81%

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Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Qiu¹,

Shao²,

Yang³

et al. 2011

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The toll like receptor 9(TLR9) has been suggested to play an important role in the invasion and metastasis of cancer cells in vitro. However, the expression of TLR9 in human cancer specimens has never been characterized. In this study, we investigated the expression of TLR9 in breast cancer specimens and determined the association between its expression and the clinicopathological features observed. We found that TLR9 expression was significantly higher in patients with breast cancers displaying large tumor size (P = 0.040), lymph node metastasis (P <0.001) or advanced pathological stage (P = 0.006). TLR9 expression was also increased in ER negative breast cancer specimens(P=0.043). Logistic regression analysis revealed that pathological stage(P = 0.007) and TLR9 (P = 0.001) expression were independent factors that influenced axillary lymph node metastasis of breast cancer. Patients with positive TLR9 expression had a higher progress free survival compared with the TLR9-negative cohort(P=0.037). Therefore we concluded that Lymph node metastasis more likely occur in breast cancer patients with a postive TLR9 status and its expression might serve as an indicator of poor prognosis in patients with breast cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 81%

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Qiu¹,

Shao²,

Yang³

et al. 2011

neo

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“…The specificity of the antibody was confirmed by doing immunohistochemical stainings with the same protocol on paraffin-embedded human tissue sections that contained lymphocytes. As expected, intracellular TLR9 staining could be seen in lymphocytes and this staining pattern was lost when the primary antibody was omitted (44). In the breast cancer specimens, the TLR9 staining intensity of the epithelial cells was graded in three representative 10Â microscopic fields per sample using a previously published method (45)(46)(47).…”

Section: Tlr9 Immunohistochemistrymentioning

confidence: 89%

Toll-Like Receptor 9 Mediates CpG Oligonucleotide–Induced Cellular Invasion

Ilvesaro¹,

Merrell²,

Li³

et al. 2008

Molecular Cancer Research

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105

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Toll-like receptor 9 (TLR9) belongs to the innate immune system and recognizes microbial and vertebrate DNA. We showed previously that treatment with the TLR9-agonistic ODN M362 (a CpG sequence containing oligonucleotide) induces matrix metalloproteinase-13 -mediated invasion in TLR9-expressing human cancer cell lines. Here, we further characterized the role of the TLR9 pathway in this process. We show that CpG oligonucleotides induce invasion in macrophages from wild-type C57/B6 and MyD88 knockout mice and in human MDA-MB-231 breast cancer cells lacking MyD88 expression. This effect was significantly inhibited in macrophages from TLR9 knockout mice and in human MDA-MB-231 breast cancer cells stably expressing TLR9 small interfering RNA or dominant-negative tumor necrosis factor receptor-associated factor 6 (TRAF6). Sequence modifications to the CpG oligonucleotides that targeted the stem loop and other secondary structures were shown to influence the invasioninducing effect in MDA-MB-231 cells. In contrast, methylation of the cytosine residues of the parent CpG oligonucleotide did not affect the TLR9-mediated invasion compared with the unmethylated parent CpG oligonucleotide. Finally, expression of TLR9 was studied in clinical breast cancer samples and normal breast epithelium with immunohistochemistry. TLR9 staining localized in epithelial cells in both cancer and normal samples. The mean TLR9 staining intensity was significantly increased in the breast cancer cells compared with normal breast epithelial cells. In conclusion, our results suggest that TLR9 expression is increased in breast cancer and CpG oligonucleotideinduced cellular invasion is mediated via TLR9 and TRAF6, independent of MyD88. Further, our findings suggest that the structure and/or stability of DNA may influence the induction of TLR9-mediated invasion in breast cancer. (Mol Cancer Res 2008;6(10):1534 -43)

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“…Sections of 4 m in thickness representing tumor, dysplastic or nonneoplastic areas were immunostained by a commercial mouse monoclonal TLR9 antibody (IMG-305A; Imgenex, San Diego, Calif., USA) with a dilution of 1: 200 [23] . CD31 staining to visualize the blood vessels was performed with a monoclonal mouse IgG1 antibody obtained from DakoCytomation (Glostrup, Denmark; M 0823, clone JC70A, using the dilution of 1: 300).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Toll-Like Receptor 9 Is a Novel Biomarker for Esophageal Squamous Cell Dysplasia and Squamous Cell Carcinoma Progression

Takala¹,

Kauppila²,

Soini³

et al. 2011

J Innate Immun

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Background: Stimulation of Toll-like receptor 9 (TLR9) has been linked to invasion in various cancer cells in vitro. We investigated TLR9 expression in normal, dysplastic and malignant esophageal squamous epithelium. Methods: TLR9 expression was analyzed by immunohistochemistry in 46 cases of esophageal squamous cell carcinoma, including 12 cases with adjacent squamous dysplasia and 24 cases with normal esophageal epithelium. TLR9 expression was compared with tumor grade, stage, proliferation, apoptosis and vascular density. Results: In normal esophageal squamous epithelium, TLR9 staining intensity decreased linearly from the basal layers to the superficial layers (p < 0.001). Strong TLR9 expression was detected across full thickness of high-grade dysplasia, the intensity clearly differing from the normal squamous epithelium and squamous cell carcinoma (p < 0.001). All squamous cell carcinomas exhibited TLR9 expression that was positively associated with a high grade (p < 0.05), the presence of lymph node metastases (p < 0.05) and previously undetected distant metastases (p < 0.05). Conclusions: Expression of TLR9 in the basal parts of normal esophageal epithelium suggests a role related to cell proliferation and differentation. TLR9 upregulation detected in dysplastic epithelium and in disseminated carcinomas indicates that this protein may serve as a novel marker for esophageal squamous dysplasia and carcinoma with metastatic potential.

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Toll-Like Receptor-9 Expression Is Inversely Correlated with Estrogen Receptor Status in Breast Cancer

Cited by 49 publications

References 63 publications

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Toll-Like Receptor 9 Mediates CpG Oligonucleotide–Induced Cellular Invasion

Toll-Like Receptor 9 Is a Novel Biomarker for Esophageal Squamous Cell Dysplasia and Squamous Cell Carcinoma Progression

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