Identification of Novel Therapeutic Targets for Triple-Negative Breast Cancer
Annual summary rept.
M D ANDERSON CANCER CENTER HOUSTON TX
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This project aims to identify, validate, and characterize novel therapeutic targets for triple-negative breast cancer TNBC. During the research period, the most significant finding was the activation of lipoprotein receptor related protein 8 LRP8 and very low density lipoprotein receptor VLDLR signaling in triple-negative breast cancer which results in activation of glycolytic and lipid metabolism to drive TNBC tumor cell growth. Previously, the two membrane receptors were found to be highly overexpressed in human TNBC tumors and identified as the top-tier candidate targets from a custom high-throughput siRNA loss-offunction screen in 18 breast cancer cell lines. Specifically, the most significant finding during the report period was apolipoprotein E isoform 4 ApoE4 mediated tumor cell stimulation and growth. In LRP8- and VLDLR-expressing breast cancer cell lines, ApoE4 stimulates cells in nutrient-poor conditions to allow them to proliferate through glycolytic and fatty acid synthesis pathways. In shLRP8 MDA-MB-231 xenografts, preliminary results show that tumor volume was significantly reduced and tumor cell necrosis was significantly higher than xenografts established by parental or shCON cells. The results suggest that LRP8 APOE signaling may be an important therapeutic target for TNBC.
- Medicine and Medical Research
- Stress Physiology