Suppression of growth and progression of breast cancer xenografts by orally administered complex sphingolipids

Abstract

Bioactive sphingolipid metabolites are generated in the intestinal tract after hydrolysis of complex sphingolipids and significantly reduced colon cancer in rodent models. In the present study we investigated if these metabolites can reach distant sites in the body in sufficient concentrations to suppress tumor formation, progression and possibly metastasis. Human breast epithelial cells representing early (MCF10AT1), intermediate (MCF7), late (MDA‐MB‐468) and metastatic stages (MDA‐MB‐231) of breast cancer were injected into the mammary fatpad of nude mice. After xenografts had reached a size of approx. 0.5cm, the diet was supplemented with 0.1% sphingolipids. Orally administered sphingolipids affected tumor number and volume in a stage‐dependent manner, with the less aggressive xenografts responding with both lower tumor number and volume while the more advanced xenografts responded with a reduction of tumor size only. To test if sphingolipids would be more effective as chemopreventive agents, the mice were fed the sphingolipids before injection of the tumor cells. This led to a reduced tumor number even with the most aggressive cell lines. Immunohistochemical analysis of proliferation and apoptosis showed a significant reduction of proliferation especially in the MCF10AT1 and MCF7 xenografts, without a significant increase in the rate of apoptosis. This reduction of proliferation was also seen in our previous studies in colon cancer models and may represent an important mechanism to suppress tumor formation, and progression. Supported by grant BCT0503453 from the Susan G. Komen Foundation and NCI/NIH R03 CA101125.