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

Ilvesaro, Joanna; Merrell, Melinda A.; Li, Li; Wakchoure, Savita; Graves, David E.; Brooks, S.R; Rahko, Eeva; Jukkola-Vuorinen, Arja; Vuopala, Katri; Harris, Kevin W.; Selander, Katri S.

doi:10.1158/1541-7786.mcr-07-2005

Cited by 77 publications

(122 citation statements)

References 51 publications

(85 reference statements)

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“…The stepwise logistic regression revealed that TLR9 expression as well as advanced pathological stage was significantly correlated with the trend of breast cancer to metastasis. These data suggests that TLR9 may induce the invasion and metastasis of breast cancer as shown in some previouse in vitro studies, which may involve an up-regulation of matrix metalloproteinase-13 activity [10,13,14].…”

Section: Discussionsupporting

confidence: 73%

“…Since TLR9 was recognized as the receptor for unmethylated CpG DNA of most bacteria and DNA viruses, many attention has been given to explore its anti-tumor effect. However, there were also some reports concerning the direct effect of TLR9 ligation on tumor behavior such as invasion and metastasis [5,10,[13][14][15]. Our study is the first to investigate the expression of TLR9 in large breast cancer specimens and correlate TLR9 with clinicopathological features of breast cancer.…”

Section: Discussionmentioning

confidence: 73%

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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

neo

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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: 73%

Section: Discussionmentioning

confidence: 73%

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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“…For stable silencing TLR9 in T47D cells, the cells were transfected with TLR9-RNAi or Neo plasmid using Lipofectamine reagent, as described previously (16). Forty-eight hours after transfection, cells were subcloned onto 96-well plates using the limiting dilution method and single-cell clones were established.…”

Section: Methodsmentioning

confidence: 99%

Toll-like receptor 9 agonist inhibits ERα-mediated transactivation by activating NF-κB in breast cancer cell lines

Qiu

Wang²,

Guo³

et al. 2009

Oncol Rep

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Abstract. Primarily, Toll-like receptor 9 (TLR9) is a specific receptor for microbial DNA in human immune cells. TLR9 has been found to be a promising target in tumor immunotherapy but the direct effect of its activation on tumor cells remains unknown. In this study, we examined the effect of TLR9 ligation on estrogen receptor · (ER·)-mediated transactivation of breast cancer. Luciferase report gene assays, RNA interference of TLR9 and Chromatin immunoprecipitation were performed to measure the effect of TLR9 ligation on ER·-mediated transactivity of T47D and MCF-7 cells. Bromodeoxyuridine incorporation assay was used to examine the effect of TLR9 ligation on estrogen (E2)-induced proliferation of breast cancer cells. We also investigated the mechanism for the effect of TLR9 ligation on ER·-mediated transactivity. We found that ER·-mediated transcription via estrogen response element of human breast cancer cells line T47D was significantly suppressed when treated with 17ß-estradiol in combination with TLR9 agonist CpG oligonucleotides and this effect of CpG was dependent on TLR9. Furthermore, nuclear factor κB (NF-κB) inhibitor BAY 11-7082 could abolish the inhibitory effect of CpG oligonucleotides on ER·-mediated transactivation. We also confirmed the effect of CpG oligonucleotides on ER·-mediated transactivation in the breast cancer cell line MCF-7 forced to stably overexpress TLR9. Finally, we observed that CpG oligonucleotides were also able to inhibit estrogeninduced proliferation of breast cancer cells as a consequence of decreased ER·-mediated transactivation. Taken together, our data suggest that TLR9 signal pathway, by activating NF-κB, negatively regulates ER·-mediated transactivation of breast cancer. Thus, TLR9 agonist inhibits the proliferation of breast cancer cells in response to estrogen.

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“…In cancer, tumor cells death results in release of numerous proteic or nucleic DAMPs that activate TLRs of both immune/stromal cells and epithelial cancer cells. Increasing evidence has indicated that TLRs expression by cancer cells and immune cells seems to be twofold by either promoting or inhibiting tumor progression [6,15,16].…”

Section: Introductionmentioning

confidence: 99%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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

Cited by 77 publications

References 51 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 agonist inhibits ERα-mediated transactivation by activating NF-κB in breast cancer cell lines

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

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