Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion

Yang, Huan; Zhou, Haichao; Feng, Ping; Zhou, Xiao-Ni; Wen, Hongtao; Xie, Xing; Shen, Haiying; Zhu, Xue-Ming

doi:10.1186/1756-9966-29-92

Cited by 166 publications

(154 citation statements)

References 25 publications

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“…In contrast to its role in tumor-associated immune cells, TLR4 promotes growth (6) and chemotherapeutic resistance (7, 8) in ER-negative breast cancer cell lines, in accordance with studies of ovarian cancer (9, 10). Based on these studies, therapies targeting TLR4 appear to be novel viable strategies with significant potential for treating cancer, and have in fact been proposed as such (6)(7)(8).In this study, we demonstrate that TLR4 promotes cell growth in TP53 mutant breast cancer, but inhibits cell growth in TP53 wild-type breast cancer. Moreover, we demonstrate TP53-dependent differential cytokine secretion by breast cancer cells on TLR4 activation, resulting in the secretion of proinflammatory cytokines in TP53 mutant cells and the tumor antagonistic cytokine, IFN-γ, in TP53 wild-type cells.…”

mentioning

confidence: 56%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.reast cancer has one of the highest incidence rates of cancer in women worldwide, with more than 1.5 million women diagnosed with the disease in 2012. Owing to its high incidence, breast cancer is also one of the leading causes of cancer-related deaths, with 40,000 women predicted to die of the disease in 2014 in the US alone. The diagnosis and treatment of breast cancer has been significantly improved by the identification of three major subtypes of the disease based on receptor expression: estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [tumors lacking ER, progesterone receptor (PR), and HER2]. Of these subtypes, ER-positive breast cancer accounts for 70-80% of all diagnosed breast tumors.ER-positive breast cancer is largely responsive to endocrine therapy; however, intrinsic or acquired resistance occurs in onethird of cases and contributes significantly to breast cancerassociated mortality. Therefore, identifying therapeutic targets to prevent ER-positive breast cancer mortality is a major focus of scientific investigation. ER-positive breast tumors with a high mutation load are associated with poor patient survival, and a high mutation load likely affects the response to endocrine therapy (1). Because known drivers of endocrine resistance (e.g., PR negativity and HER2 amplification) are not enriched in this subset, the identification of no...

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confidence: 56%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite this, we saw no association serum LPS, glial activation and pain. Instead, astrocytic activation appeared to occur bimodally, with increases in GFAP staining seen at 6 and 72 h. This suggests that cellular events associated with apoptosis (which peaks at 6 h), or inflammation may be more important in TLR4- (45)(46)(47). In addition, although not assessed in the current study, future work will need to clarify the role of TLR4 in normal gastrointestinal motility patterns given recent research implicating TLR4 in altered motility patterns following opioid treatment (48, 49).…”

Section: Discussionmentioning

confidence: 98%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

123

124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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“…They also play a role in detecting endogenous damage associated patterns, oftentimes associated with cellular release of heat-shock proteins, components of the extracellular matrix, and mitochondrial DNA. 32 Divergent roles for TLR4 expression have been described in different cancers, with increased TLR4 expression in breast cancer correlating with disease progression, 33 while in colon cancer TLR4 expression correlated with less metastasis. 34 A more meaningful model may call for examining the role that TLR4 plays in mesenchymal stem cells where different Toll-like receptors play different immunomodulatory roles.…”

Section: Discussionmentioning

confidence: 99%

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

et al. 2015

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Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value D 1.7 £ 10 ¡6 ), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies.

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Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion

Cited by 166 publications

References 25 publications

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

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