Abstract
Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.
Highlights
Breast cancer is one of the most common cancers diagnosed among women, accounting for nearly 1 in 3 cancers [1]
We found that a secretory protein called C-C motif chemokine ligand 20 (CCL20) responds to taxane chemotherapy in triple-negative breast cancer (TNBC) and promotes the expression of a drug efflux pump through a specific signaling pathway (CCL20-protein kinase Cz [PKCz]/p38 mitogen-activated protein kinase [MAPK]-nuclear factor kappa B [NF-κB]-ATP-binding cassette subfamily B member 1 [ABCB1])
Our results suggest that blocking CCL20 or its downstream signal can significantly improve the therapeutic efficacy of TNBC
Summary
Breast cancer is one of the most common cancers diagnosed among women, accounting for nearly 1 in 3 cancers [1]. Regulation of ATP-binding cassette (ABC) transporters and β-tubulin III subunit, disorder in enzymes critical in DNA replication and repair, alterations in genes involved in apoptosis, and drug inactivation/detoxification and abnormal regulation of key signaling pathways such as aberrant activation of nuclear factor kappa B (NF-κB) or AKT activity all participate in chemoresistance in TNBC [6] These regulatory mechanisms can help tumor cells escape apoptosis induced by chemotherapeutic drugs to acquire the ability of chemoresistance in TNBCs. Besides, more and more studies showed that breast cancer stem cells (BCSCs), which represent a distinct population that can be prospectively isolated from the total tumor cell population and have clonal long-term repopulation and self-renewal capacity, are responsible for chemotherapy resistance [7]. The differential and diverse regulation of BCSCs influences the chemoresistance of TNBCs
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