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James W Antoon Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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William D Meacham Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Melyssa R Bratton Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Evelyn M Slaughter Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Lyndsay V Rhodes Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Hasina B Ashe Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Thomas E Wiese Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Matthew E Burow Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Barbara S Beckman Tulane Department of Pharmacology, Section of Hematology and Medical Oncology, Department of Pharmacy, Tulane Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, Louisiana 70112, USA

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Recently, crosstalk between sphingolipid signaling pathways and steroid hormones has been illuminated as a possible therapeutic target. Sphingosine kinase (SK), the key enzyme metabolizing pro-apoptotic ceramide to pro-survival sphingosine-1-phosphate (S1P), is a promising therapeutic target for solid tumor cancers. In this study, we examined the ability of pharmacological inhibition of S1P formation to block estrogen signaling as a targeted breast cancer therapy. We found that the Sphk1/2 selective inhibitor (SK inhibitor (SKI))-II, blocked breast cancer viability, clonogenic survival and proliferation. Furthermore, SKI-II dose-dependently decreased estrogen-stimulated estrogen response element transcriptional activity and diminished mRNA levels of the estrogen receptor (ER)-regulated genes progesterone receptor and steroid derived factor-1. This inhibitor binds the ER directly in the antagonist ligand-binding domain. Taken together, our results suggest that SKIs have the ability to act as novel ER signaling inhibitors in breast carcinoma.

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