title: Benzyl butyl phthalate promotes breast cancer stem cell expansion via SPHK1/S1P/S1PR3 signaling.
abstract: Understanding the regulatory mechanisms unique to breast cancer stem cells (BCSCs) is required to control breast cancer metastasis. We found that phthalates promote BCSCs in human breast cancer cell cultures and xenograft tumors. A toxic phthalate, benzyl butyl phthalate (BBP), activated aryl hydrocarbon receptor in breast cancer cells to stimulate sphingosine kinase 1 (SPHK1)/sphingosine 1-phosphate (S1P)/sphingosine-1-phosphate receptor 3 (S1PR3) signaling and enhance formation of metastasis-initiating BCSCs. BBP induced histone modifications in S1PR3 in side population (SP) cells, but not in non-SP cells. SPHK1 or S1PR3 knockdown in breast cancer cells effectively reduced tumor growth and lung metastasis in vivo. Our findings suggest S1PR3 is a determinant of phthalate-driven breast cancer metastasis and a possible therapeutic target for regulating BCSC populations. Furthermore, the association between breast carcinogenesis and environmental pollutants has important implications for public health.
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: National Applied Research Laboratories, National Laboratory Animal Center, Nangang, Taipei 11529, Taiwan.
authors.forename: Hsiao-Li
authors.initials: HL
authors.lastname: Chuang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Hung-Sheng
authors.initials: HS
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Jau-Nan
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D043484:Proprotein Convertases / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D010795:Phthalic Acids; D043484:Proprotein Convertases; D049349:Receptors, Lysosphingolipid; D012697:Serine Endopeptidases; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C577483:sphingosine-1-phosphate receptor-3, human; C115575:membrane-bound transcription factor peptidase, site 1; C027561:butylbenzyl phthalate
keywords: aryl hydrocarbon receptor; breast cancer stem cells; sphingosine 1-phosphate; sphingosine kinase 1; sphingosine-1-phosphate receptor 3