The Regulation And Molecular Mechanisms Of CCL20 On The Chemotherapeutic Efficacy Of Triple-negative Breast Cancer

Chemotherapy resistance of triple-negative breast cancer(TNBC)has always been a major problem to be solved in clinical treatment,which seriously endangers the survival of patients.The drug resistance of TNBC to taxanes(including paclitaxel and docetaxel)has not been solved,and the specific mechanism is unclear.Our results suggest that CCL20 is significantly elevated in serum of breast cancer patients who have received taxanes-containing chemotherapy and did not show pathologically complete response(pCR).CCL20 is a member of chemokine family,which is related to innate immunity,arthritis,psoriasis and so on.However,its role in TNBC still remains unknown.We confirmed that taxanes could significantly induce CCL20 production in TNBC cells.Moreover,CCL20 can promote the proliferation,invasion,soft agar colony formation ability and the growth of tumors in mice.Overexpression of CCL20 activated p38 MAPK and PKC signals respectively,which subsequentially promoted the activation of p65 NF-kappa B.The CCL20-p38 MAPK/PKC-NF-kappa B signal axis promotes the self-renewal of breast cancer stem cells(BCSCs),enhances their sternness characteristics and promotes taxane resistance of BCSCs.We found that the activation of NF-kappa B induced by CCL20 promotes the transcription of ABCB1,which promotes the drug to be pumped out of cells as an efflux pump,thus leading to taxane resistance in TNBC.At the same time,NF-kappa B also mediates the transcription of CCL20,i.e.a positive feedback pathway is formed between the two,which continuously promotes taxane efflux and drug resistance.Therefore,our study shows that CCL20 can be used as a new indicator for predicting the chemotherapeutic resistance of TNBC to taxane,and targeting CCL20 or its activated downstream molecules might improve the therapeutic effect of TNBC.