Contribution of toll-like receptor signaling pathways to breast tumorigenesis and treatment

Kidd, LaCreis R.; Rogers, Erica N.; Yeyeodu, Susan; Jones, Dominique Dominique; Kimbro, K. Sean

doi:10.2147/bctt.s29172

Cited by 20 publications

(20 citation statements)

References 83 publications

(87 reference statements)

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“…numerous studies have suggested that Tlrs, which are normally associated with immunity and inflammation, may be involved in the progression and prognosis of breast cancer. Tlrs are highly expressed in breast cancer cells, and activation of these receptors can induce aggressive tumor behavior, cell proliferation, cell invasion, cell migration and metastasis (24). The 'cross-talk' between Tlrs and various other signaling pathways in breast cancer constitutes a markedly complicated signaling network system to promote secretion of inflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

Expression profile of Toll‑like receptors in human breast cancer

Shi

Fang

et al. 2019

Mol Med Report

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Toll-like receptors (Tlrs) are the most widely studied pattern recognition receptors. Mounting evidence suggests an important association between Tlrs and the occurrence and development of breast cancer. Thus, targeting these receptors may be a potential strategy for breast cancer treatment. The current study analyzed the data of 1,215 patients with breast cancer obtained from The cancer Genome atlas (TcGa) database. it was observed that, in addition to Tlr6, Tlr7 and Tlr8, the expression of the remaining Tlrs in breast cancer tissues was lower than that in normal tissues. in addition, Tlr3 and TLR9 displayed significantly different expression levels in er-/Pr-negative breast cancer compared with the control tissues, while TLR5 expression was significantly reduced in Her2-enriched breast cancer. Furthermore, Tlr10 exhibited lower expression levels in advanced stages of the disease as compared with that observed in earlier stages. Survival analysis revealed that the expression of Tlr4 and Tlr7 had a significant impact on survival, and higher expression levels suggested worse prognosis. Finally, the expression levels of Tlr1, Tlr2, Tlr4, Tlr5, Tlr6 and Tlr10 were correlated with those of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α, while the expression levels of Tlr3, Tlr7, Tlr8 and Tlr9 were correlated with those of interferon-β and c-X-c motif chemokine ligand 10. Taken together, the current study results suggest that Tlr expression may serve as a biomarker of cancer pathogenesis and progression, and may provide new insights for the treatment of breast cancer through the regulation and targeting of Tlrs.

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Section: Discussionmentioning

confidence: 99%

Expression profile of Toll‑like receptors in human breast cancer

Shi

Fang

et al. 2019

Mol Med Report

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“…Dysregulation of and genetic alterations in inflammation and immune response pathways have been linked with cancer susceptibility (6–9, 28). Although African-American women suffer disproportionately from more deadly forms of BrCa, only one study has explored the involvement of a single TLR-associated SNP ( TLR1/TLR6/TLR10 rs7696175) in relation to BrCa among this high risk sub-group (19).…”

Section: Discussionmentioning

confidence: 99%

“…Given that IRAK4 is a common mediator of TLR signaling from the cell surface and from endosomes (Figure 1), the fact that all TLRs except TLR8 have been shown to influence BrCa progression (9) implicates IRAK4 as an accomplice. Figure 1 illustrates representative signaling pathways from surface (TLR2 and TLR4) and endosomal (TLR3 and TLR4) TLRs [reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

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IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women

et al. 2013

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Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68- to 4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK4 and its XCT in cell transformation and innate immunity.

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“…Several studies have suggested that imbalances between inflammatory- and immune-associated proteins contribute to breast cancer and disease progression [ 3 ]. Persistent inflammatory conditions stimulate the production of cytokines and chemokines, which promote angiogenesis, metastasis, and subversion of adaptive immunity [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A Prospective Evaluation of the Association between a Single Nucleotide Polymorphism rs3775291 in Toll-Like Receptor 3 and Breast Cancer Relapse

Chen

Song

et al. 2015

PLoS ONE

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BackgroundToll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients.MethodsIn this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population.ResultsUnivariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98–6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal-A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype.ConclusionOur results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings.

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Contribution of toll-like receptor signaling pathways to breast tumorigenesis and treatment

Cited by 20 publications

References 83 publications

Expression profile of Toll‑like receptors in human breast cancer

Expression profile of Toll‑like receptors in human breast cancer

IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women

A Prospective Evaluation of the Association between a Single Nucleotide Polymorphism rs3775291 in Toll-Like Receptor 3 and Breast Cancer Relapse

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