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Serum Amyloid A1 Mediates Paclitaxel Resistance via MD2-Dependent Pathways in Triple-Negative Breast Cancer
Kangmin Chen1,2,3, Yanni Zhao1,2,3, Tianyang Jin2
1Department of Oncology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China.
Abstract:
Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.
Insights
Serum amyloid A1 (SAA1) and myeloid differentiation protein 2 (MD2) drive paclitaxel resistance in triple-negative breast cancer (TNBC). Targeting this PTX/SAA1/MD2 axis may overcome drug resistance in TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Triple-negative breast cancer (TNBC) presents therapeutic challenges due to a lack of specific targets.
- Paclitaxel (PTX) is a common treatment, but drug resistance significantly limits its efficacy.
- Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are implicated in various diseases, including cancer.
Purpose of the Study:
- To investigate the role of SAA1 in paclitaxel resistance in TNBC.
- To identify potential therapeutic targets for overcoming PTX resistance in TNBC.
Main Methods:
- Analysis of SAA1 expression in TNBC tissues and cells.
- Investigating the effect of PTX and cisplatin (CIS) on SAA1 expression.
- Evaluating the impact of MD2 blockade on PTX sensitivity in TNBC cells.
- Exploring the molecular interactions between SAA1, MD2, TLR4, MyD88, and the NF-κB pathway.
Main Results:
- SAA1 is expressed in human TNBC and induced by PTX and CIS in TNBC cells.
- PTX induces an inflammatory response in TNBC cells mediated by SAA1.
- Blocking MD2 enhances TNBC cell sensitivity to PTX, linked to SAA1 expression during PTX treatment.
- SAA1 interacts with MD2, promoting TLR4/MD2 and TLR4/MyD88 complex formation and activating the NF-κB signaling pathway, fostering an inflammatory tumor microenvironment.
Conclusions:
- The PTX/SAA1/MD2 axis is identified as a key mechanism in paclitaxel resistance in TNBC.
- This axis promotes an inflammatory microenvironment that supports cancer cell survival and resistance.
- Targeting the SAA1/MD2 interaction presents a potential therapeutic strategy to overcome PTX resistance in TNBC.
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