Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells

Zunyue Zhang,Xiang Li,Zhuoya Li,Yibing Hu,Xiang-Ping Yang,Jing Wang,Yujing Yan,Guohong Lin,Bingjiao Yin,Yaqun Wu

doi:10.1038/s41388-018-0221-4

Zunyue Zhang, Xiang Li + Show 8 more

Open Access

https://doi.org/10.1038/s41388-018-0221-4

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Abstract

Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.

Highlights

Despite many advances in the treatment of breast cancer, the prognosis for patients with metastatic disease remains poor
We found that the expression of transmembrane tumor necrosis factorα (tmTNF-α) was undetectable in peritumor breast tissue, whereas 63.8% of breast cancers contained tumor cells that expressed tmTNF-α at high levels (++/+++) (Supplementary Figures 1a and b)
We found no significant effect of altering tmTNF-α on the expression of methylguanine–DNA methyltransferase (MGMT), P-gp, TOP2a or multidrug resistance protein-1 (MRP-1), expression of the first three were higher in MCF-7 compared with MDA

Summary

Introduction

Despite many advances in the treatment of breast cancer, the prognosis for patients with metastatic disease remains poor. Cytotoxic chemotherapy is of limited benefit and chemoresistance remains a major obstacle. The anthracycline antibiotics containing doxorubicin (DOX) [1,2,3] are. Multiple mechanisms have been proposed in the resistance of DOX-induced cytotoxicity, including increased drug efflux through upregulating expression of transporters such as the Pglycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) [7, 8], altered enzymatic activity of glutathione transferase, mutations in DNA of topoisomerase (TOP) and increased expression of anti-apoptotic proteins such as Bcl-2 [9, 10]

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