Abstract P2-05-06: Does the lipid mediator sphingosine-1-phosphate have a role in obesity-related cancer progression?
Authors: Nagahashi M , Yamada A , Aoyagi T , Huang W-C , Allegood JC , Milstien S , Spiegel S , Takabe K 
Published: August 2014

INTRODUCTION: Obesity, which is the number one health risk in US ranked by the CDC, is an established independent prognostic factor for breast cancer patients. While the link between obesity and elevated breast cancer mortality is well known, the underlying mechanisms are poorly understood. The pleiotropic bioactive lipid mediator sphingosine-1-phosphate (S1P) has emerged as a key regulatory molecule in cancer progression and inflammation. S1P is generated by two sphingosine kinases, SphK1 and SphK2, and exerts its functions by binding to specific G protein-coupled receptors (S1PR1-5). We have recently shown that SphK1, but not SphK2, produces S1P that is exported from breast cancer cells, mediated by the ATP-binding cassette transporter, ABCC1. Furthermore, we discovered that another S1P transporter, Spns2, is important for the lymphatic network formation in the LNs. FTY720, which after phosphorylation is a S1PR1 functional antagonist, was recently approved by FDA for multiple sclerosis. FTY720 also has been suggested to have some anti-cancer actions. Our hypothesis is that obesity up-regulates SphK1, which produces more S1P; the elevated levels of S1P in both tumor and its microenvironment stimulate breast cancer progression. FTY720 is expected to disrupt the SphK1/S1P/S1PR1 axis, which is strengthened by obesity, and to reduce cancer metastasis and prolong survival. We tested our hypothesis by utilizing animal models of breast cancer with obesity treated with FTY720.

METHODS: We utilized two different syngeneic breast cancer mouse models: 4T1-luc2 cells in BALB/c mice and E0771 cells in C57Bl/6 mice, both inoculated into mammary fat pads of mice fed with normal or high fat diet. FTY720 was given orally. Western blot, QPCR and LC-ESI-MS/MS assays were used.

RESULTS: We observed that breast tumors in obese animals expressed higher levels of SphK1 and S1P transporters, such as ABCC1 and Spns2, as compared to animals on a normal diet. The levels of S1P in the plasma of obese mice were also elevated, which appears to be a consequence of the higher production of S1P by SphK1 in the tumor and its microenvironment. Importantly, tumor progression in both models was suppressed significantly by administration of FTY720. Interestingly, the cancer progression was suppressed more efficiently in the obese mice than the lean mice. Further, LC-ESI-MS/MS analysis showed that FTY720 suppressed S1P levels not only in the blood, but also in the tumor interstitial fluid.

CONCLUSIONS: These results suggest that the S1P axis is strengthened by obesity, and has a role in cancer progression. Targeting the S1P axis with FTY720 may be useful for treating breast cancer in individuals with obesity. M.N. is a Japan Society for the Promotion of Science Postdoctoral Fellow. This work was supported by NIH grants R37GM043880, R01CA61774 (to S.S.) and R01CA160688 (to K.T.).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-06.