Research explores complex relationship between cholesterol and breast cancer risk

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Jun 15 2023

In a review article published in The Journal of Steroid Biochemistry and Molecular Biology, scientists discuss the role of cholesterol and its metabolites in breast cancer.

Study: Is cholesterol a risk factor for breast cancer incidence and outcome? Image Credit: BOKEH STOCK / Shutterstock.com

Background

Cholesterol is an essential component of the cell membrane and aids in the synthesis of hormones, thereby contributing to cellular homeostasis.

The role of cholesterol in breast cancer remains poorly understood, with many studies reporting contradictory results. Whereas some studies have established a positive association between blood cholesterol levels and breast cancer risk, others studies have found an inverse relationship between total cholesterol and high-density lipoprotein (HDL)-cholesterol levels and breast cancer risk.

Epidemiological evidence

Menopausal women who consume diets that are high in cholesterol are at an increased risk of breast cancer risk. Likewise, in vivo models of breast cancer have demonstrated that a high-cholesterol diet increases tumor growth by 20%, as well as the likelihood of metastasis. Similarly, high-fat diets have been found to increase serum cholesterol and leptin levels, as well as facilitate breast cancer development, particularly in postmenopausal mice and obese mice.

Abnormal serum cholesterol levels have often been reported in patients with metabolic syndrome. Notably, the presence of metabolic syndrome appears to increase the risk of breast cancer, particularly in postmenopausal women. With each additional element of the metabolic syndrome, the risk of developing breast cancer similarly rises.

Although reduced HDL-cholesterol levels have been found to increase breast cancer risk, increased levels of total cholesterol and low-density lipoprotein (LDL)-cholesterol are associated with a reduced risk of breast cancer.

Low HDL-cholesterol levels are often accompanied by high levels of estrogens in obese or overweight women. These characteristics are both important risk factors for the onset and progression of breast cancer onset. In women with triple-negative breast cancer, high triglyceride level and low HDL-cholesterol level increase the risk of mortality. 

An increased level of apolipoprotein A-I (apoA-I), which is the main protein of HDL, has also been found to increase breast cancer risk. Comparatively, an increased level of apolipoprotein B (apoB) has been found to reduce breast cancer risk. 

Cholesterol metabolites

Various cholesterol metabolites have been found to influence breast cancer risk. Oxysterol, for example, exhibits tumor-promoting activity, whereas dendrogenin A associated with tumor-suppressing activity. Likewise, 27-hydroxycholesterol, an endogenous oxysterol, increases estrogen receptor- and liver X receptor-dependent tumor growth in mice.

Additionally, 5,6-epoxycholesterol, another type of oxysterol, can be converted into cholestane-3β,5α,6β-triol by cholesterol-5,6-epoxide hydrolase, which can be further converted to oncosterone. In estrogen receptor-positive and triple-negative breast cancer cells, oncosterone increases cellular proliferation and promotes cancer progression.  

Alternatively, 5,6-epoxycholesterol can be converted into dendrogenin A by the enzyme DNA-dependent ATPase (DDA) synthase. This cholesterol metabolite can act as a tumor suppressor by promoting cellular differentiation and cancer cell death.    

How does cholesterol affect breast cancer risk?

Cholesterol has been shown to increase cancer cell proliferation by stimulating AKT phosphorylation. LDL has also been found to stimulate the proliferation and migration of breast cancer cells.

Accumulation of cholesteryl esters in breast cancer cells has been found to increase cancer aggressiveness. In estrogen receptor-negative breast cancer cells, higher levels of triglycerides and cholesteryl esters as compared to estrogen receptor-positive cells. An increased expression of LDL receptor has also been found in breast cancer cells enriched with cholesteryl esters, which could be due to higher activity of acyl-coenzyme A: cholesterol acyltransferase.

In breast cancer cells, 27-hydroxycholesterol has been found to increase matrix metalloproteinase 9 (MMP9) expression, activate signal transducer and activator of transcription 3 (STAT3), increase migration, invasion and epithelial-to-mesenchymal transition, as well as activate oncoprotein Myc by increasing its stability. Furthermore, 27-hydroxycholesterol increases breast cancer cell proliferation by increasing the expression of the E3 ubiquitin-protein ligase MDM2, thereby reducing the expression of p53 and stimulating the interaction between p53 and MDM2.   

The reduced expression of protein StARD3, which regulates cholesterol entry into mitochondria, is associated with reduced proliferation, increased metastasis, and increased apoptosis of breast cancer cells. Notably, StARD3 overexpression of this protein occurs in 30% of breast cancer cases.  

Cholesterol alters breast cancer risk by modulating various signaling pathways. For example, cholesterol binds to certain scaffolding proteins to increase cancer cell proliferation. Additionally, cholesterol modification can alter lipid raft structure and function to influence cancer development and progression.