Cholesterol and Its Derivatives: Multifaceted Players in Breast Cancer Progression

Abstract

Cholesterol is an essential lipid primarily synthesized in the liver through the mevalonate pathway. Besides being a precursor of steroid hormones, bile acid, and vitamin D, it is an essential structural component of cell membranes, is enriched in membrane lipid rafts, and plays a key role in intracellular signal transduction. The lipid homeostasis is finely regulated end appears to be impaired in several types of tumors, including breast cancer. In this review, we will analyse the multifaceted roles of cholesterol and its derivatives in breast cancer progression. As an example of the bivalent role of cholesterol in the cell membrane of cancer cells, on the one hand, it reduces membrane fluidity, which has been associated with a more aggressive tumor phenotype in terms of cell motility and migration, leading to metastasis formation. On the other hand, it makes the membrane less permeable to small water-soluble molecules that would otherwise freely cross, resulting in a loss of chemotherapeutics permeability. Regarding cholesterol derivatives, a lower vitamin D is associated with an increased risk of breast cancer, while steroid hormones, coupled with the overexpression of their receptors, play a crucial role in breast cancer progression. Despite the role of cholesterol and derivatives molecules in breast cancer development is still controversial, the use of cholesterol targeting drugs like statins and zoledronic acid appears as a challenging promising tool for breast cancer treatment.

Keywords: breast cancer; breast cancer therapy; cancer metabolism; cholesterol; cholesterol metabolism; mevalonate (MVA) pathway; statins.

Figure 1

Cholesterol homeostasis main processes. (1) SREBP processing at the ER membrane and Golgi apparatus; in high cholesterol condition, SREBP is retained at the ER membrane by INSIG and SCAP, which sense oxysterols and sterols, respectively. At low cholesterol condition, SREBP can be transported to the Golgi apparatus and cleaved by S1P and S2P proteases. Cleaved SREBP can enter the nucleus and trigger the transcription of crucial MVA pathway genes. (2) Main steps of cholesterol synthesis through the MVA pathway, of which HMGCR represents the rate-limiting enzyme. (3) LDL-cholesterol intake via LDL-receptor mediated endocytosis. (4) Cholesterol efflux by ABCA1 transporter, which employs ATP molecules to deliver cholesterol and lipids on apoA-I, triggering the assembly of nascent HDL. (5) ACAT enzyme mediated cholesterol esterification to fatty acids tightly packaged and stored in the core of intracellular lipid droplets, which represent a ready storage of lipids that can be used without investing energy in biosynthesis. (6) Cholesterol conversion in its main derivatives, some of which may play a role in BC pathology and progression. The main cholesterol homeostasis inhibitors and their targets are underlined in blue, while drugs and substances used in clinical trials (see Table 1 ) are shown in green. Created with BioRender.com.