Research Papers:

Benzyl butyl phthalate promotes breast cancer stem cell expansion via SPHK1/S1P/S1PR3 signaling

Yu-Chih Wang, Cheng-Fang Tsai, Hsiao-Li Chuang, Yi-Chih Chang, Hung-Sheng Chen, Jau-Nan Lee and Eing-Mei Tsai _

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Oncotarget. 2016; 7:29563-29576. https://doi.org/10.18632/oncotarget.9007

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Yu-Chih Wang1,*, Cheng-Fang Tsai2,*, Hsiao-Li Chuang3, Yi-Chih Chang4, Hung-Sheng Chen2, Jau-Nan Lee1, Eing-Mei Tsai1,2

1Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

2Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

3National Applied Research Laboratories, National Laboratory Animal Center, Nangang, Taipei 11529, Taiwan

4Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan

*These authors contributed equally to this work

Correspondence to:

Eing-Mei Tsai, email: [email protected]

Keywords: aryl hydrocarbon receptor, sphingosine kinase 1, sphingosine 1-phosphate, sphingosine-1-phosphate receptor 3, breast cancer stem cells

Received: December 06, 2015     Accepted: March 28, 2016     Published: April 26, 2016


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.

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