CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer

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. Breast cancers are divided into several different subtypes according to the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2). One subtype of breast cancer is known as triple-negative breast cancer (TNBC) because of lack of expression of all three receptors. TNBC is highly malignant and susceptible to developing drug resistance during chemotherapy. However, the reasons for resistance have not been well explained. We found that a secretory protein called C-C motif chemokine ligand 20 (CCL20) responds to taxane chemotherapy in TNBC and promotes the expression of a drug efflux pump through a specific signaling pathway (CCL20-protein kinase Cζ [PKCζ]/p38 mitogen-activated protein kinase [MAPK]-nuclear factor kappa B [NF-κB]-ATP-binding cassette subfamily B member 1 [ABCB1]). Increasing levels of CCL20 result in expanding breast cancer stem-like cell population and chemotherapeutic resistance in breast cancer cells. Breast cancer stem-like cells are a special population of cells with self-renewal and differentiation potential within the tumor, which are often the culprit of tumor reoccurrence, drug resistance, and metastasis. Our results suggest that blocking CCL20 or its downstream signal can significantly improve the therapeutic efficacy of TNBC.