CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer

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.

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…Another therapeutic approach is the use of anti-CCR4 antibodies or CCR4 antagonists ( receptor for CCL17/TARC and CCL22/MDC) in cancer therapy [257][258][259] to reduce the accumulation of T reg and thus enhance the immunotherapy and anticancer response of the immune system. Some researchers also postulate targeting the CCL20/LARC→CCR6 axis [260,261], which causes chemoresistance and migration of neoplastic cells, and so any disorder in the function of CCL20/LARC should increase the activity of anticancer drugs. The data presented above also show that hypoxia increases the expression of CCR7 and thus causes metastasis to lymph nodes.…”

Emerging Landscapes of Tumor Immunity and Metabolism

“…Showalter Loral E et al found that the expression of histone lysine-specific demethylase 1 (LSD1) is inversely proportional to chemokine CCL5 levels that attract CTLs, while the use of LSD1 inhibitors combined with PD-1 antibodies can significantly increase the infiltration of CD8 + T cells and reduce the tolerance of TNBC to chemotherapy drugs (62,63). In addition, Chen Weilong et al found that during the taxane-containing chemotherapy, the CC motif chemokine ligand 20 (CCL20) was significantly elevated, which is activated by protein kinase Cζ (PKCζ) or p38 mitogen Protein kinase (MAPK) -mediated NF-κB activation to promote self-renewal and maintenance of CSC or breast cancer stem-like cells, while NF-κB activation increases CCL20 expression, forming a positive feedback loop between the NF-κB and CCL20 pathways, providing continuous momentum for chemo-resistance in breast cancer cells (64)(65)(66). Yu Shiyi et al found that heat shock protein 90 (HSP90) and histone deacetylase 6 (HDAC6) are promising anticancer drug targets.…”

Prediction of prognostic signatures in triple-negative breast cancer based on the differential expression analysis via NanoString nCounter immune panel

“…CCR6 interacted with CCL20 in the pCR group and is a receptor of CCL20 ; overexpression of CCL20 augments mitogen-activated protein kinase and protein kinase C signalling, resulting in tumour progression [ 15 – 17 ]. Significant enrichment in molecular functions determined by Gene Ontology analysis of genes and their interaction partners in the STRING database are summarised in Table 8 .…”