CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer

Weilong Chen; Yuanyuan Qin; Dong Wang; Lei Zhou; Yin Liu; Sheng Chen; Liang Yin; Yaoxing Xiao; Xiao-Hong Yao; Xiaoli Yang; Wei Ma; Weifeng Chen; Xueyan He; Lixing Zhang; Qifeng Yang; Xiuwu Bian; Zhi-Ming Shao; Suling Liu

doi:10.1371/journal.pbio.2005869

CCL20 triggered by chemotherapy hinders the therapeutic efficacy of breast cancer

PLoS Biol. 2018 Jul 27;16(7):e2005869. doi: 10.1371/journal.pbio.2005869. eCollection 2018 Jul.

Authors

Weilong Chen¹, Yuanyuan Qin¹, Dong Wang^{1

2}, Lei Zhou^{1

2}, Yin Liu³, Sheng Chen³, Liang Yin⁴, Yaoxing Xiao⁵, Xiao-Hong Yao⁶, Xiaoli Yang², Wei Ma², Weifeng Chen⁷, Xueyan He², Lixing Zhang², Qifeng Yang⁸, Xiuwu Bian⁶, Zhi-Ming Shao^{2

3}, Suling Liu²

Affiliations

¹ School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, Anhui, China.
² Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, China.
³ Department of Oncology, Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ The department of breast surgery, The First People's Hospital of Zhenjiang City, Zhenjiang, China.
⁵ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
⁷ National Engineering Research Center for Functional Food, School of Food Science and Technology, Jiangnan University, Wuxi, China.
⁸ Department of Breast Surgery, Qilu Hospital, Shandong University, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / metabolism
Aldehyde Dehydrogenase / metabolism
Animals
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Bridged-Ring Compounds / pharmacology
Bridged-Ring Compounds / therapeutic use
Cell Line, Tumor
Chemokine CCL20 / metabolism*
Chemotherapy, Adjuvant
Disease Progression
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
NF-kappa B / metabolism
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Prognosis
Protein Kinase C / metabolism
Remission Induction
Taxoids / pharmacology
Taxoids / therapeutic use
Treatment Outcome
Triple Negative Breast Neoplasms / drug therapy
Triple Negative Breast Neoplasms / pathology
Up-Regulation
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Bridged-Ring Compounds
Chemokine CCL20
NF-kappa B
Taxoids
taxane
Aldehyde Dehydrogenase
protein kinase C zeta
Protein Kinase C
p38 Mitogen-Activated Protein Kinases

Grants and funding

NSFC grant www.nsfc.gov.cn (grant number 81530075). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MOST grant www.most.gov.cn/eng (grant number 2015CB553800). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Key Research and Development Program of China (grant number Stem Cell and Translational Research 2016YFA0101202). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NSFC grants (grant number 81472741). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Fudan University Research Foundation (grant number IDH 1340042). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Research Foundation of the Fudan University Shanghai Cancer Center (grant number YJRC1603). SL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.