TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer

Rajput, Sandeep; Volk-Draper, Lisa D.; Ran, Sophia

doi:10.1158/1535-7163.mct-12-1019

Cited by 132 publications

(149 citation statements)

References 46 publications

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“…Previous studies suggested that paclitaxel induces expression of TLR-4, which in turn increases NF-κB activity (41). However, exposure of MDA-MB-231 or SUM-159 cells to concentrations of paclitaxel that enriched for BCSCs did not increase TLR-4 mRNA expression ( Fig.…”

Section: /Prmentioning

confidence: 74%

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

Samanta¹,

Gilkes²,

Chaturvedi³

et al. 2014

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

445

404

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Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER + /PR + breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance 1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF-1α or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival.digoxin | mammary fat pad implantation | tumor relapse

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Section: /Prmentioning

confidence: 74%

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

Samanta¹,

Gilkes²,

Chaturvedi³

et al. 2014

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

445

404

View full text Add to dashboard Cite

show abstract

“…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: 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%

“…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%

mentioning

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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Microneedle‐Directed Drug Delivery to Tumor‐Draining Lymph Node for Synergistic Combination Chemoimmunotherapy for Metastatic Cancer

Jung

Lim

Kim

et al. 2022

Advanced Therapeutics

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Chemoimmunotherapy based on the combination of anticancer agents and immune modulators is considered as a promising anticancer therapeutic approach that leads to tumor cell death and tumor‐specific immune responses, suppressing the growth of metastatic tumors in distal sites. However, the undesirable systemic immune responses and cytotoxicity caused by chemoimmunotherapy should be reduced prior to clinical translation. This study aimed to design an amphiphilic triblock copolymer‐based dissolving microneedle (MN), which can generate nanomicelles (PTX/R848@NMC) containing a poorly water‐soluble anticancer drug, paclitaxel (PTX), and an immune modulator, resiquimod (R848). The combination of PTX and R848 synergistically induces immunogenic cell death (ICD) in melanoma cells (B16F10) at reduced PTX concentrations without compromising the viability and functions of dendritic cells (DCs). After cutaneous application of MN to tumor‐bearing mice, the PTX/R848@NMC generated from the dissolution of MN can migrate to tumor‐draining lymph nodes, resulting in the death of metastatic tumor cells and the activation and maturation of DCs. Tumor‐specific immune responses can effectively suppress the growth of primary and metastatic secondary tumors.

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TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer

Cited by 132 publications

References 46 publications

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

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

Microneedle‐Directed Drug Delivery to Tumor‐Draining Lymph Node for Synergistic Combination Chemoimmunotherapy for Metastatic Cancer

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