15357163mct121019-sup-fig_s1.pdf (343.87 kB)
Supplementary Figure S1 from TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer
journal contributionposted on 2023-04-03, 14:03 authored by Sandeep Rajput, Lisa D. Volk-Draper, Sophia Ran
Supplementary Figure S1 - PDF file 343K, Functional analysis of TLR4 protein in MDA-MB-231 cells
ARTICLE ABSTRACTOverexpression of Toll-like receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis. We found that TLR4 is overexpressed in the majority of clinical breast cancer samples and in 68% of the examined breast cancer lines. TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely used drug paclitaxel. LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in the breast cancer environment. We reasoned that paclitaxel-dependent activation of TLR4 is more relevant to breast cancer chemoresistance that could be mediated by activation of the NF-κB pathway leading to upregulation of prosurvival genes. To test this hypothesis, we correlated TLR4 expression with resistance to paclitaxel in two modified breast cancer lines with either depleted or overexpressed TLR4 protein. Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated prosurvival genes concomitant with 2- to 3-fold reduced IC50 to paclitaxel in vitro and a 6-fold decrease in recurrence rate in vivo. Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and prosurvival genes along with a 3-fold increase of IC50 to paclitaxel in vitro and enhanced tumor resistance to paclitaxel therapy in vivo. Importantly, both tumor models showed that many paclitaxel-upregulated inflammatory cytokines were coinduced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops. Collectively, these results show that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway. These findings suggest that blocking TLR4 could significantly improve response to paclitaxel therapy. Mol Cancer Ther; 12(8); 1676–87. ©2013 AACR.
Breast CancerCell SignalingAutocrine-paracrine signalingChemotherapyBiochemical modulators of the therapeutic indexComputational MethodsGene expression profilingDrug MechanismsCellular responses to anticancer drugsDrug ResistanceNovel mechanismsRegulation of gene expression in drug resistanceReversal of drug resistanceDrug TargetsProgression, Invasion & MetastasisInflammation and tumor development