Paclitaxel Therapy Promotes Breast Cancer Metastasis in a TLR4-Dependent Manner

Volk-Draper, Lisa D.; Hall, Kelly; Griggs, Caitlin; Rajput, Sandeep; Kohio, Pascaline; DeNardo, David G.; Ran, Sophia

doi:10.1158/0008-5472.can-14-0067

Cited by 203 publications

(191 citation statements)

References 48 publications

(77 reference statements)

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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.…”

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confidence: 53%

“…Other studies have identified TLR4 as a promoter of chemotherapeutic resistance in MDA-MB-231 cells (7,8). Those studies used HCC1806, another TP53 mutant, ER-negative breast cancer cell line with very low baseline levels of TLR4, as a negative control.…”

Section: Discussionmentioning

confidence: 99%

“…Those studies used HCC1806, another TP53 mutant, ER-negative breast cancer cell line with very low baseline levels of TLR4, as a negative control. Rajput et al (8) reported that TLR4 knockdown in MDA-MB-231 cells sensitizes them to chemotherapy, whereas overexpression of TLR4 in HCC1806 cells renders them resistant to chemotherapy. That group has since published a follow-up study demonstrating a role for TLR4 in promoting migration on exposure to cytotoxic therapy (8).…”

Section: Discussionmentioning

confidence: 99%

“…TLR4 is mutated in ∼1% of all breast cancers, both ER-positive and ER-negative, but is mutated at >5% frequency in the poor-outcome subset of ERpositive tumors. Although TLR4 has been proposed to be a breast cancer oncogene (6)(7)(8), the TLR4 mutations in breast tumors from The Cancer Genome Atlas (TCGA) dataset appear to disrupt gene function, and manifest as either early truncating or missense mutations in protein interaction regions (Fig. 1A).…”

Section: Tlr4 Is Frequently Mutated In Er-positive High Mutation Loadmentioning

confidence: 99%

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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: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Tlr4 Is Frequently Mutated In Er-positive High Mutation Loadmentioning

confidence: 99%

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confidence: 99%

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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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Direct Immunoactivation by Chemotherapeutic Drugs in Cancer Treatment

Wang,

Song,

et al. 2023

Advanced Therapeutics

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The immune system plays a crucial role in recognizing and eliminating pathogenic substances and malignant cells in the body. For cancer treatment, immunotherapy is becoming the standard treatment for many types of cancer and is often combined with chemotherapy. Although chemotherapeutic agents are often reported to have adverse effects, including immunosuppression, they can also play a positive role in immunotherapy by directly stimulating the immune system. This has been demonstrated in preclinical and clinical studies in the past decades. Chemotherapeutics can activate immune cells through different immune receptors and signaling pathways depending on their chemical structure and formulation. In this review, we summarize and discuss the direct immunoactivation effects of chemotherapeutics and possible mechanisms behind these effects. Finally, we prospect chemo‐immunotherapeutic combinations for the more effective and safer treatment of cancer.This article is protected by copyright. All rights reserved

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TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

Yin

Shen

et al. 2017

The Anatomical Record

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Bacteria/virus-induced chronic inflammation is involved in both tumor initiation and tumor progression. Toll-like receptor 4 (TLR4) has been implicated in the development of several types of cancer. In this study, we explored the impact of TLR4 activation by lipopolysaccharide (LPS) on breast cancer metastasis and associated signaling molecules. We first examined TLR4 expression levels in breast tissue using a human breast tissue microarray and breast cell lines. We then studied the role of TLR4 activation by LPS stimulation in breast cancer metastasis using both in vitro and in vivo models. Finally, we investigated signaling molecules involved in the process using Western blotting and fluorescent immunohistochemistry staining. The results showed that TLR4 expression levels increased in breast cancer tissue compared to normal breast tissue. In addition, our results also showed that TLR4 pathway activation by LPS stimulation in MCF7 and MDA-MB-231 breast cancer cells caused the following actions: (1) promotes migration of breast cancer cells, (2) triggers the β-catenin signaling pathway via PI3K/Akt/GSK3β, and (3) promotes transcription of downstream β-catenin target genes leading to breast cancer metastasis. This study substantiates and further extends the relationship between TLR4 activation by LPS and breast cancer using both in vitro and in vivo models. The results suggest that the Akt/GSK3β/β-catenin signal transduction pathway may serve as a viable clinical treatment target in breast cancer. Anat Rec, 300:1219-1229, 2017. © 2017 Wiley Periodicals, Inc.

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Paclitaxel Therapy Promotes Breast Cancer Metastasis in a TLR4-Dependent Manner

Cited by 203 publications

References 48 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

Direct Immunoactivation by Chemotherapeutic Drugs in Cancer Treatment

TLR4 Promotes Breast Cancer Metastasis via Akt/GSK3β/β‐Catenin Pathway upon LPS Stimulation

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