Abstract
Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide‐I (AT-I), a novel TLR4-antagonizing agent, is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear. Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments. Results: We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit N-Nitroso-N-methylurea-induced rat mammary tumor progression through TLR4/NF-κB pathway. Conclusion: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.
Highlights
Breast cancer, a malignancy stemming from mammary epithelial tissues, stood as the most common cancer in women, and the second contributory factor of cancer related women death all over the world (Siegel et al, 2020)
We found that Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were over expressed in human breast cancer tissues, and activation of TLR4/NF-κB pathway was correlated with advanced TNM-stages
We found that the expression of TLR4 and NF-κB in high TNM stages was significantly higher than that in low TNM-stages of breast cancer (Figures 1A,B)
Summary
A malignancy stemming from mammary epithelial tissues, stood as the most common cancer in women, and the second contributory factor of cancer related women death all over the world (Siegel et al, 2020). The current available treatments with two selective ER modulators (SERMs), tamoxifen and raloxifene, approved by the FDA for breast cancer chemoprevention, remain unsatisfactory due to the drug resistance and side-effects such as hepatic injury (Yang et al, 2013). Toll-liked receptors (TLRs), mainly expressing in human immune related cells, plays a crucial role in the first line of host defense by recognizing pathogen-associated molecular patterns (PAMPs) (Kawai and Akira, 2010; O’neill et al, 2013). The expression of TLR4 was the highest among other TLRs in human breast cancer, and TLR4 activation could subsequently activate nuclear factor-κB (NF-κB) and produce pro-inflammatory cytokines, stimulating inflammation (Yang et al, 2010; Eskiler et al, 2019). Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. The effects of AT-I on mammary tumorigenesis remain unclear
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