title: Benzyl butyl phthalate increases the chemoresistance to doxorubicin/cyclophosphamide by increasing breast cancer-associated dendritic cell-derived CXCL1/GROα and S100A8/A9.
abstract: Phthalates are used as plasticizers in the manufacture of flexible vinyl, which is used in food contact applications. Phthalates have been demonstrated to have an adverse impact on human health, particularly in terms of cancer development. In the present study, we showed for the first time that benzyl butyl phthalate (BBP) potentiates the effect of tumor‑associated dendritic cells (TADCs) on the chemoresistance of breast cancer. Specific knockdown analysis revealed that S100A9 is the major factor responsible for the chemoresistance of doxorubicin/cyclophosphamide induced by BBP-stimulated TADCs in breast cancer. BBP exposure also increased tumor infiltrating myeloid-derived suppressor cell (MDSC) secretion of S100A8/A9, thereby exacerbating the resistance of breast cancer to doxorubicin with cyclophosphamide. In addition, BBP also stimulated the production of CXCL1/GROα by TADCs, which increased the angiogenesis of breast cancer in a mouse model. Inhibition of CXCL1/GROα by a neutralizing antibody, decreased the BBP-induced angiogenesis induced by BBP after chemotherapy in the mouse model. These results, for the first time, provide evidence that BBP influences the efficacy of chemotherapy by remodeling the tumor microenvironment of breast cancer.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Ho
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Jian
authors.affiliation: Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Meng-Chi
authors.initials: MC
authors.lastname: Yen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Wei-An
authors.initials: WA
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D040501:Calgranulin A / Q000096:biosynthesis* / Q000235:genetics; D040502:Calgranulin B / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000235:genetics; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D010795:Phthalic Acids / Q000008:administration & dosage*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; C475829:CXCL1 protein, human; D040501:Calgranulin A; D040502:Calgranulin B; D054360:Chemokine CXCL1; D010795:Phthalic Acids; D004317:Doxorubicin; D003520:Cyclophosphamide; C027561:butylbenzyl phthalate