Reopening Pandora's box: Is there a role for HDL in breast cancer?

Plasma lipid and lipoprotein profiles are recognized as key modulators in breast cancer (BC) development. Notably, the association between high-density lipoprotein cholesterol (HDLc) and BC remains controversial, with studies reporting positive, negative, or no correlation. This inconsistency may arise from the clinical metrics used to quantify high-density lipoproteins (HDL), such as HDLc and apolipoprotein (apo) A-1, which may not accurately reflect HDL functionality in modulating the tumor microenvironment. Moreover, HDL particles isolated from plasma may undergo modifications influenced by tumor activity, varying with disease stage, severity, and treatment. In this review, we are critically reopening Pandora´s box analyzing evidence on HDLc plasma levels and HDL functionality in BC. Specifically, HDL contributes to tumor regulation by removing excess cellular cholesterol, thereby limiting sterol availability for cell replication and metastasis. Additionally, HDL exerts antioxidant and anti-inflammatory effects and acts as a carrier of bioactive proteins, lipids, and microRNAs, facilitating their delivery to target cells and modulating intracellular signaling and gene expression. Collectively, HDL functionality may serve as a predictor of therapeutic response and clinical outcomes in BC.