Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Chemoresistance is a significant challenge in breast cancer treatment.
• Soluble tumor necrosis factor-α (sTNF-α) is linked to drug resistance, but the role of transmembrane tumor necrosis factor-α (tmTNF-α) is unknown.

Purpose of the Study:

• To investigate the role of tmTNF-α in mediating chemoresistance in breast cancer.
• To elucidate the mechanisms by which tmTNF-α contributes to drug resistance.
• To evaluate tmTNF-α as a therapeutic target in combination with chemotherapy.

Main Methods:

• Analysis of tmTNF-α expression in breast cancer tissues.
• Manipulation of tmTNF-α expression in human breast cancer cells.
• Investigation of signaling pathways (ERK, NF-κB) involved in tmTNF-α-mediated resistance.
• Assessment of combined tmTNF-α suppression and chemotherapy in a xenograft mouse model.

Main Results:

• Over 50% of patients showed high tmTNF-α expression, correlating with anthracycline resistance.
• Altering tmTNF-α levels affected sensitivity to doxorubicin (DOX).
• Overexpression of tmTNF-α N-terminal fragment (NTF) induced DOX resistance.
• The tmTNF-α/NTF-ERK-GST-π and tmTNF-α/NTF-NF-κB pathways were crucial for DOX resistance.
• Combined tmTNF-α suppression and DOX chemotherapy improved efficacy in a mouse model.

Conclusions:

• tmTNF-α mediates doxorubicin resistance in breast cancer via reverse signaling through the ERK and NF-κB pathways.
• Targeting tmTNF-α represents a potential therapeutic strategy to overcome chemoresistance in breast cancer.