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Prevention of Breast Cancer by Sphingolipids: Importance of EGFR Regulation
Sphingolipids are involved in the regulation of cell growth, differentiation and cell death. Our studies were the first to show that oral administration of sphingolipids significantly inhibits colon cancer in mice and reduce the progression of pre-neoplastic breast xenografts that may be associated with the concurrent inhibition of EGFR and Her-2neu. However, it is not known if sphingolipids in amounts that do not cause toxic side effects also affect more malignant cells. Our central hypothesis is that sphingolipids administered orally inhibit EGFR and Her-2neu activation in breast cancer cells, thereby inhibiting growth factor-activated signaling pathways as a measure to suppress proliferation and progression of breast cancer cells. We also hypothesize that the upstream regulation of EGFR plus the regulation of multiple targets in the EGFR-activated survival and proliferation signaling pathways by sphingolipids is generating a more potent growth inhibitory signal than treatment with specific EGFR inhibitors and, thus, more effectively inhibits tumor proliferation, progression and metastasis. This will be tested in the following specific aims: 1: Determine to what extent sphingolipids suppress breast tumor growth and progression in immunodeficient nude mice. The potential of orally administered sphingolipids to suppress the growth and progression of ER+ MCF7 cells and ER- MDA-MB-468 cells transplanted orthotopically into nude mice, and MDA-MD-435 xenografts that spontaneously develop metastasis at high frequency will be compared to intraperitoneal injections of sphingolipid metabolites. 2: Determine the effects of non-toxic doses of sphingolipid metabolites on proliferation and survival signaling pathways of breast cancer cells in vitro. The mechanisms of how non-toxic concentrations of sphingolipid metabolites alter EGFR and Her-2neu activation, receptor trafficking, and modulate activated signaling pathways will be evaluated. We will determine how these changes affect proliferation and apoptosis, adhesion and motility in vitro, and, importantly, how this is associated with the suppression of tumor growth, progression and metastasis in vivo. These studies will delineate the potential of sphingolipids to inhibit breast cancer, outline possible limitations, and will provide the mechanistic foundation for the design of a prevention and treatment strategy using non-toxic sphingolipids as a safe alternative to conventional anti-cancer drugs.
Breast cancer is the most common female cancer worldwide. It is a slow and heterogeneous disease and many women die when the tumor spreads from the breast to other sites of the body. Only limited success has been achieved with new chemotherapeutic drugs. Both new and conventional drugs often cause serious side effects that restrict long-term treatment. The development of an effective non-toxic strategy that prevents tumor growth and spreading is therefore needed. Sphingolipids are components of all eukaryotic cells, and can be found in most foods in appreciable amounts. They warrant consideration as anti-cancer agents because they regulate cell growth, cell death and differentiation- all processes that are deregulated in cancer and enable cancer cells to grow in an uncontrolled fashion. We have shown in earlier studies that orally administered sphingolipids significantly reduce the incidence of colon cancer in mice, and preliminary studies show that they also inhibit progression of cells representing the earliest stages of breast cancer to more malignant cancers without causing any toxic side effects. It is, however, unknown if these doses can also suppress later stages of breast cancer and the spreading of tumors throughout the body. Therefore, in the studies proposed here we will transplant breast cancer cells representing more aggressive stages of human breast cancer into mice. We will analyze to what extent orally administered sphingolipids inhibit breast tumor growth, and prevent the formation and growth of secondary tumors (metastasis) without causing deleterious side effects. Then we will investigate the mechanisms of sphingolipid-induced cancer suppression by determining changes in signaling pathways that are critical for the unlimited cancer cell growth. These studies will provide crucial information on how sphingolipids suppress tumor growth without affecting normal cells and will identify markers to predict sphingolipid efficacy in vivo. The use of natural sphingolipids in non-toxic doses is a novel concept, and the studies proposed here will provide the mechanistic basis for the development of a strategy to prevent breast cancer, suppress metastasis and the reappearance of cancer and may allow for a long-term regimen in high-risk women, and a better compliance with the treatment.