Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties

Abstract

Growing evidence indicates that resistin-an obesity-related cytokine-is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial-mesenchymal transition and stemness in breast cancer cells-mechanisms critical to tumorigenesis and metastasis-through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

“…We identified activation of STAT3 as the mechanism of resistin action that is mediated by its two receptors CAP1 and TLR4. This is in agreement with a recent report in breast cancer (Wang et al, 2018) where resistin was shown to bind to its receptor TLR4 resulting in STAT3 activation and induction of EMT and stemness. In an earlier report (Kuo et al, 2013), resistin was reported to induce EMT in lung cancer cells resulting in increased invasion and migration, thus confirming our observation that resistin has a profound effect on cancer cells' proliferation, migration, and invasion.…”

“…There are few other reports identifying CAP1 as a bonafide receptor for resistin (Lee et al, ; Munjas et al, ). In contrast, TLR4 appears to be a more widely studied receptor of resistin, in not just human cancer models (Gong et al, ; Wang et al, ) but various disease models as well (Y. Jiang et al, ; Li et al, ; Miao et al, ; Zuniga et al, ). Based on the relative number of reports vouching for these two receptors to be the receptors for resistin, clearly TLR4 seems to be relatively well studied.…”

“…There are few other reports identifying CAP1 as a bonafide receptor for resistin (Lee et al, 2014;Munjas et al, 2017). In contrast, TLR4 appears to be a more widely studied receptor of resistin, in not just human cancer models (Gong et al, 2018;Wang et al, 2018) but various disease models as well (Y. Jiang et al, 2016;Li et al, 2017;Miao et al, 2018;Zuniga et al, 2017).…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Both leptin and resistin exacerbates an inflammatory microenvironment by favoring the secretion of other pro-inflammatory adipokines. Additionally, leptin favors breast cancer progression by inducing cellular proliferation by binding to its receptor followed by downstream signaling through NFκB, STAT3, ERK1/ERK2, and phosphoinositide-3-kinase (PI3K) pathways (56,57). Both elevated leptin and resistin concentrations was associated with the promotion of cancer stem cell survival and the promotion of invasion and migration via epithelial to mesenchymal transition in breast cancer cells (55,56,58), which contributes to the development of treatment resistance.…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…A 12‐week‐long treatment comparing efficacy of pioglitazone and metformin in decreasing serum resistin levels, fasting blood glucose, and insulin concentration was completed in T2DM children, but results of the clinical trial have not been posted (identifier # NCT01396564). Antibodies against resistin and its putative receptors such as toll‐like receptor 4 and adenylyl cyclase‐associated protein 1 can be candidate therapeutic agents to antagonize resistin function . Antioxidants may also be useful in lowering resistin levels.…”