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.

Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study

“…3,19 Preclinical evidence suggests that some phthalates promote breast tumor growth through estrogen receptor (ER) signaling. [20][21][22][23][24][25] Estrogenindependent breast cancer promotion mechanisms have also been reported for phthalates, 21,[26][27][28][29] as have antiestrogenic effects. 23 Epidemiologic evidence is inconsistent regarding the effect of phthalates on breast cancer incidence.…”

RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis

“…To ensure the causality of the impaired tumorigenic phenotype of RNF40-silenced HCC1954 cells due to an impaired actin regulatory pathway, we examined the effects of restoring this signaling cascade. For this purpose, we treated HCC1954 cells with an allosteric sphingosine 1-phosphate receptor-3 agonist (CYM-5441), which was shown to activate actin polymerization as well as increase cancer stem cell expansion in BC (41,42). Treatment of RNF40-depleted HCC1954 cells with CYM-5441 significantly rescued apoptosis as measured by Annexin V staining (Fig.…”

The potential for estrogen disrupting chemicals to contribute to migration, invasion and metastasis of human breast cancer cells

“…Furthermore, BBP has been reported to increase growth of tumours and lung-derived metastases in an in vivo mouse xenograft model using breast cancer stem cells. The mechanism was linked to an arylhydrocarbon receptor-mediated increase in sphingosine-1-phosphate receptor 3 (S1PR3) signaling since downregulation of this pathway reduced both the tumour growth and the lung metastasis but the role of estrogen in this remains unknown [54] .…”