US EPA

3230378 

Journal Article 

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

Wang, YC; Tsai, CF; Chuang, HL; Chang, YC; Chen, HS; Lee, JN; Tsai, EM 

2016 

1 

Oncotarget
ISSN: 1949-2553 

7 

20 

29563-29576 

English 

27129165 

10.18632/oncotarget.9007 

WOS:000377742600064 

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. 

aryl hydrocarbon receptor; sphingosine kinase 1; sphingosine 1-phosphate; sphingosine-1-phosphate receptor 3; breast cancer stem cells