Obesity, which induces low-grade inflammation, is a known risk factor for worse prognosis in many cancers including breast. We found that sphingosine-1-phosphate (S1P) produced by sphingosine kinases (SphKs) plays a critical role in obesity-related inflammation and breast cancer. Obesity increased S1P in the tumor microenvironment, as well as in the primary tumors. FTY720, a functional antagonist of S1PR1, dramatically decreased cancer progression by reducing expressions of SphK1 and S1PR1, and inflammatory cytokines including IL-6. Our results suggest a critical role for S1P in obesity-related inflammation and FTY720, an S1P axis inhibitor, appears to be a promising treatment for breast cancer in the obese condition, could be due to its effect on reactivate ERa expression and sensitize breast cancer cells to tamoxifen therapy.