title: Mesenchymal stem cell-induced doxorubicin resistance in triple negative breast cancer.
abstract: Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.
authors.affiliation: Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 50006, Taiwan.
authors.forename: Dar-Ren
authors.identifier: 0000-0002-0897-4374
authors.initials: DR
authors.lastname: Chen
authors.affiliation: Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung 40402, Taiwan.
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua 50006, Taiwan.
authors.forename: Wei-Lan
authors.identifier: 0000-0003-4398-7610
authors.initials: WL
authors.lastname: Yeh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D016209:Interleukin-8; D004317:Doxorubicin