SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer

Abstract

Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.

Keywords: HDL cholesterol; SR-BI; breast cancer; cholesterol; lipoprotein.

Figure 1

Role of SR-BI in the regulation of cellular signaling pathways and regulation of its expression in cancer cells. PPARα and/or PPARγ and SREBP pathways may be activated to promote SCARB1 gene expression. In addition, as described in macrophages, high levels of glucose may also contribute to SR-BI up-regulation via pathways that remain to be identified. Several miRNAs (such as miR-192, -185, -125a, and -455) have been found to regulate the post-transcriptional expression of SR-BI. Interestingly, these miRs are down-regulated in several cancers. Once associated with the plasma membrane, SR-BI contributes to the uptake of cholesteryl ester (CE) from HDL. A relevant residue in SR-BI for this interaction is Cys384 (denoted with an orange label). CE may be converted into free cholesterol (FC) which can be incorporated in the plasma membrane or organelles (such as mitochondria), stored in lipid droplets (LD), or used as substrate for steroids and other cholesterol metabolites. The C-terminal domain of SR-BI (denoted in yellow) interacts with PDZK1, which can activate PI3-kinase (PI3K) and c-Src pathways to promote proliferation and migration. Another yet unexplored role of SR-BI is its interaction with apoptotic cells. This interaction may also contribute to the activation of signaling pathways that promote malignant features.