Abstract P6-06-04: The role of sphingosine kinase 1 in breast carcinogenesis

Abstract

Abstract Introduction: The bioactive sphingolipids, ceramide/sphingosine and sphingosine 1-phosphate (S1P) possess opposite effects on cell fate. Sphingosine kinase 1 (SphK1) is an enzyme that principally regulates the balance or the "rheostat" of the sphingolipids by phosphorylating sphingosine to form S1P. In this study, we investigated the effect of SphK1 deficiency on HER2/neu-induced mammary carcinogenesis using a MMTV-neu transgenic (Tg) mice model. Methods: MMTV-neu Tg mice were crossbred with SphK1 knockout (KO) mice to generate MMTV-neu Tg mice with KO or wild-type for SphK1 gene. The number and size of the palpable tumors were recorded weekly until mice reached 35 weeks of age or the largest tumor diameter reached 20 mm in size. At necropsy, tumors and blood were collected for analysis. The sphingolipid profiles in blood were analyzed using tandem mass spectrometry. Results: The incidences of mammary tumor development in the homozygous SphK1 KO (1/13; 8%) and heterozygous SphK1 KO (11/44; 26%) were significantly reduced (P=0.0112 and 0.0208, respectively) when compared to wild-type mice (8/13; 62%). The mammary tumor multiplicity was significantly reduced in homozygous SphK1 KO (0.08±0.08; P=0.0036) when compared to wild-type mice (0.69±0.17). The S1P levels in blood were significantly decreased in homozygous SphK1 KO mice (P<0.0001), while sphingosine levels were significantly increased in the blood of heterozygous SphK1 KO mice (P<0.001). In both homozygous and heterozygous SphK1 KO mice, the blood level of C16:0-Ceramide was significantly increased (P<0.001). Conclusion: The results provide novel evidence that SphK1 mediates HER2/neu-induced mammary carcinogenesis by regulating the ceramide/sphingosine-S1P "rheostat". Thus, we propose that SphK1 inhibition may be a novel therapeutic option in the treatment of HER2 breast tumors. Citation Format: Yoshiko Shimizu, Hideki Furuya, Paulette M Tamashiro, Kayoko Iino, Charles J Rosser, Toshihiko Kawamori. The role of sphingosine kinase 1 in breast carcinogenesis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-06-04.