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Lipid-induced breast cancer metastasis
Tumor Cell Biology I
Metastasis turns a primary tumor into a deadly disease. Prerequisite for metastasis formation is the cancer cell migration from the primary tumor to the target tissue. The P.I.'s group has shown for the first time that the bile acid (BA) precursor oxysterol (OS) is synthesized in human osteoblast MG63 cells and induces migration of human breast cancer cells. In new results, the P.I. found that bile acids (BAs) are released from human bone tissue, induce migration of breast cancer cells, and elevate bone metastasis in a mouse tumor model. The P.I.'s results show that activation of Cox-2 is necessary but not sufficient to mediate BA-induced migration. This suggests that an additional mechanism is activated by OS/BAs. The objectives of the present study are: i) to understand the mechanism by which OS/BAs induce breast cancer cell migration, and ii) to determine the significance of OS/BA biosynthesis or accumulation in bone tissue for breast cancer metastasis. The main hypothesis is that OS/BA-induced formation of r eceptor- a ssociated m embrane domains (RAMs) in breast cancer cells activates their cell signaling pathways for migration and metastasis to the bone . In addition to testing this hypothesis, the P.I.'s group will determine whether treatment with cholesterol biosynthesis inhibitors (statins), BA receptor (FXR)-antagonists, or Cox-2 inhibitors prevents cancer cell migration and metastasis formation. Hence, the P.I. anticipates that this study on a novel mechanism for OS/BA-induced cancer cell migration will define new treatment options for cancer therapy.
Bone metastasis of breast cancer turns a treatable into a deadly disease. The factors inducing migration of breast cancer cells into bone are largely unknown. The P.I. has found that bile acids are elevated in bone tissue and induce migration and bone metastasis of breast cancer cells. This is unexpected because bile acids are mainly synthesized in the liver and by intestinal bacteria. The aims of the present study are: i) to understand the mechanism by which bile acids induce breast cancer cell migration, and ii) to determine the significance of bile acid generation or enrichment in bone tissue for breast cancer metastasis. The main hypothesis is that bile acids change the composition of the cancer cell surface, which results in the activation of cancer cell migration toward bone tissue. In addition to understand how bile acids promote migration and metastasis, the P.I. will develop new treatment strategies that prevent this effect. This includes pharmacological intervention with bile acid biosynthesis and cell signaling, but also dietary advice to reduce the exposure to bile acids.