Proteomic and lipidomic analysis of low-density lipoprotein identifies potential biomarkers of early estrogen receptor-positive breast cancer

Estrogen receptor (ER)-positive breast cancer (BC) is a prevalent and fatal cancer among women, and there is a need to identify molecules involved in the disease pathophysiology which could also serve as biomarkers for early detection. Detection of cancer markers in whole plasma produces excessive information, and identifying important markers involved in cancer progression is challenging. We identified a BC-specific low-density lipoprotein (LDL) particle isolated by ultracentrifugation from the plasma of ER-positive BC patients. This LDL has an aberrant proteome and lipidome, significantly different from that of LDL from healthy women, including a high association with the pro-tumor chemokines CXCL4 and CXCL7, and an enrichment with the lipid subclasses phosphatidylethanolamine, ceramide, triglycerides, lysophosphatidylcholine, phosphatidylserine, phosphatidic acid, and sphingomyelin. In contrast, phosphatidylinositol species were significantly less abundant in LDL from tumor patients than in control. Moreover, BC-associated LDL has a distinct effect on macrophage phenotype, inducing an increased gene expression of IL1β, IL8 and CD206 and decreased gene expression of TNFα, a gene signature characteristic of tumor-associated macrophages (TAMs). This suggests that this formerly unrecognized form of LDL may represent LDL particles that are recruited by the tumor microenvironment to support tumor progression by inducing discrete subsets of TAMs. In conclusion, these data offer BC-associated LDL as an early biomarker detection platform for ER-positive BC. Furthermore, LDL-associated proteins and lipids that promote BC progression may also serve in the future as novel targets for BC therapies.