You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer}
Article:
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.
Introduction:
Breast cancer is one of the most common cancers diagnosed among women, accounting for nearly 1 in 3 cancers[1]. The recurrence, metastasis, and drug resistance in the course of chemotherapy have brought great threat to breast cancer patients[2, 3], especially as chemoresistance limits the effectiveness of chemotherapeutic agents to a large extent. Although the triple-negative breast cancers( TNBCs) are generally very susceptible to chemotherapy initially because of the highly proliferative capacity, early complete response( CR) does not correlate with overall survival( OS)[4]. Chemoresistance emerges during therapy because tumor cells are able to maintain viability following chemotherapeutic exposure via undergoing alternative cellular fates such as autophagy, cellular senescence, and therapeutic induced senescence( TIS), although cytotoxic chemotherapy aims to kill cancer cells through apoptosis[5]. There are several specific ways to regulate chemoresistance of TNBC. 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 also influences the chemoresistance of TNBCs. In addition to intrinsic genetic changes in cells as described above, recent data suggest that chemoresistance can also result from cell-extrinsic factors such as growth factors and cytokines[8]. Both malignant and cancer-associated normal cells in the tumor niche affect the balance of cytokines that play pivotal roles in regulating tumor cell proliferation, survival, and chemoresistance[9–11]. Gilbert and Hemann’s study in lymphoma model described an interleukin 6( IL-6)-triggered cytokine-chain response that can promote therapeutic resistance to genotoxic chemotherapy of lymphoma cells[10]. In addition to IL-6, some other cytokines are also able to regulate tumor progression and chemotherapeutic resistance in an autocrine manner in multiple cancers[12]. Although both the extrinsic and intrinsic factors have revealed the possible clues to chemotherapeutic resistance in TNBC, there are still some critical questions to be answered in clinical practice. During the taxane( taxol or docetaxel) therapies for TNBC patients, the risk factors for determining drug resistance and the underlying mechanisms remain unknown. And there is a lack of effective markers to indicate the chemoresistance of TNBC. Through studies analyzing breast cancer patients’ serum, tumor tissue sample, survival prognosis, and pathologic response to taxane, we identified a chemokine, C-C motif chemokine ligand 20( CCL20), that might predict the risk of taxane resistance in TNBC patients. Moreover, our studies in both TNBC cell line–derived xenograft( CDX) and patient-derived xenograft( PDX) mouse models showed that the blockade to CCL20 or CCL20-mediated downstream molecules could attenuate BCSCs and reverse chemoresistance and significantly improved the chemotherapeutic efficacy of taxane to TNBC. CCL20, a member of the C-C motif chemokine subfamily, participates in many diseases’ progression—including rheumatoid arthritis( RA), psoriasis, and immune response—and promotes the malignancy in colorectal cancer and lung cancer[13, 14]. However, the role of CCL20 in cancers has not been well elucidated. More importantly, little work has been done on the role of CCL20 in regulating the tumor progression and chemoresistance in breast cancer, especially TNBC, and the regulation mechanisms still remain unknown. Our current studies showed that taxane-induced CCL20 could promote self-renewal of BCSCs through the activation of p65 NF-κB, which was mediated by protein kinase Cζ( PKCζ) and p38 mitogen-activated protein kinase( MAPK) activity. The activation of p65 NF-κB further promoted transcription of both ATP-binding cassette subfamily B member 1( ABCB1) and CCL20, which sequentially increased extracellular efflux of taxane and enhanced CCL20 effect via a positive feedback loop, leading to the taxane-resistance of TNBCs and promoting breast cancer progression with worse prognosis.
Discussion:
TNBC has become a worldwide threat because of its high invasiveness, recurrence, drug resistance, and lack of effective treatment prescription[27]. Taxanes are the commonly used chemotherapeutic agents for TNBC[28]. The chemotherapeutic resistance during taxane treatment seriously affected the OS of cancer patients and brought huge complications to the clinician. Thus, it is urgent to demonstrate the mechanisms such as defining the key molecules in mediating taxane resistance in treating TNBCs. In response to the influence of repression and stimuli from chemotherapeutic agents, cancer cells will undergo multiple changes, such as alteration of the cytokine secretion. Through cytokine antibody array, we observed the correlation between CCL20 in patient serum and the indication of therapeutic response. In our studies, CCL20 emerged as the most responsive cytokine to taxane treatment, which is dosage dependent and time dependent. However, as far as the taxane stimulation on CCL20 is concerned, not only in TNBC but the phenomenon of CCL20 induction via taxane treatment also occurred in non-TNBC, actually, and the expression level of CCL20 in taxol-resistant sublines of colon cancer and ovarian cancer was significantly elevated( S8 Fig). These suggest that CCL20 may confer taxane resistance in various molecule types of breast cancer and even across multiple cancers, in which further exploration and study are needed. Previous studies showed that CCL20 promoted proliferation and migration of normal breast epithelial cells[29, 30]. Little work has revealed the regulation of CCL20 on breast cancer. Our studies showed that CCL20 stimulated the proliferation, invasion, and anchorage-independent growth in TNBC and promoted tumor outgrowth in vivo. In addition, we discovered CCL20 also exhibited strengthening in resistance to taxane, demonstrating its pivotal role in the regulation of breast cancer malignancy. And our results demonstrated for the first time that CCL20 promoted chemoresistance in BCSCs by enhancing self-renewal and stemness characteristics of BCSCs. The range of tumor types displaying aberrant NF-κB activity is extensive and comprises many solid tumors, as well as lymphomas and leukemias[31, 32]. NF-κB signaling exhibits the intricate transcriptional control of gene expression and diverse posttranslational modifications in a stimulus-specific or context-dependent way, for which the influence on the tumor progression is also complex tumor promotion or suppression, chemoresistant or chemosensitive effect, and even playing the biphasic role with dynamic regulation in tumor progression[22, 33]. In our results, p65 NF-κB mediated CCL20-induced TNBC resistance to taxane. In this process, PKCζ and p38 delivered the CCL20 stimulus in parallel. We demonstrated that, under the stimulation of taxane-induced CCL20, the p65 NF-κB was mainly shown to promote resistance to apoptosis induced by taxane treatment. Combined with the inhibition of p65 NF-κB activity, the therapeutic effect of docetaxel was significantly improved in vivo, which was consistent with the elevated therapeutic efficacy under the combinational treatment of docetaxel and direct CCL20 blockage in vivo. These discoveries shed light on direct targeting CCL20 or small molecule inhibition of CCL20-induced signaling being able to potentiate chemotherapeutic efficacy in breast cancer. In our study, one of the consequences following CCL20-induced p65 NF-κB activation was the up-regulation of ABCB1, which was involved in the efflux of a variety of drugs, including taxane[25, 26]. The observation that the intracellular abundance of docetaxel was significantly decreased after overexpression of CCL20 in our study well demonstrated why CCL20-induced NF-κB activation promoted taxane resistance. Our studies offer a novel strategy to solve taxane resistance in breast cancer, including TNBC—that is, the combination of taxane treatment and the adjuvant pharmacological inhibition of ABCB1 may greatly improve the chemotherapeutic efficacy in breast cancer. In conclusion, our results demonstrated for the first time that CCL20 promoted chemoresistance in BCSCs through the positive feedback loop mediated by PKCζ/p38-NF-κB. Importantly, our findings suggest that CCL20 can be used as a novel chemoresistance marker for the adjuvant evaluation of therapeutic efficacy in taxane treatment and as a therapeutic target to improve the efficacy of taxane therapy for TNBC 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 .