Description:

The proposed research project aims to examine the mechanisms linking obesity, Type 2 diabetes and increased breast cancer risk, in order to identify targets for therapies that will improve survival in these women. Elevated serum cholesterol is frequently seen in people with obesity and Type 2 diabetes. These patients may have elevated low density lipoprotein (LDL) or very low density lipoprotein (VLDL). These abnormal elevations in serum cholesterol have been associated with an increased risk of hormone receptor negative and Her2 overexpressing breast cancers and a poor prognosis in breast cancer patients. It is hypothesized that increased cholesterol delivery to breast cancers by VLDL and/or LDL is driving breast cancer growth and spread, particularly in breast cancers with high levels of the low-density lipoprotein receptor (LDLR) that mediates cholesterol uptake from VLDL and LDL. This cholesterol uptake may promote tumor growth by activating signaling pathways that promote survival and proliferation. In addition, cholesterol may be metabolized into biologically active metabolites (one of which is 25-hydroxycholesterol) that may promote tumor metastasis. Therefore, the research hypothesis for this proposal is that elevated circulating cholesterol in the form of VLDL or LDL cholesterol promotes breast cancer growth and metastasis by delivery of cholesterol to cancer cells via the LDLR.