Investigating the Role of Tumor-Intrinsic Cholesterol Metabolism in Breast Cancer Development within the Lipid-Depleted Environment

Abstract

Obesity increases the risk for various cancers, including breast cancer, and exacerbates cancer progression and prognosis. Dyslipidemia, the dysregulation of lipid levels in the blood, is commonly observed in individuals with obesity and is correlated with increased tumor growth and aggressiveness in breast cancer patients. Thus, it is imperative to understand how dysregulated lipid classes distinctly regulate cancer development in the tumor microenvironment. We developed an in vitro system that utilizes lipid-depleted (LD) human plasma-like media to study the role and necessity of specific lipids in regulating breast cancer viability and growth. Between two breast cancer cell lines (EO771 and PY8119), we found that extracellular lipid depletion reduces cancer cell viability and produces tumor cell type (EO771)-specific upregulation of cholesterol biosynthesis. We hypothesize that upregulated cholesterol biosynthesis activity plays a compensatory role in preserving cell viability in the LD condition. To investigate this, we assessed how intracellular inhibition and knockdown of cholesterol pathway enzymes, as well as extracellular cholesterol supplementation, affected breast cancer cell growth in the LD condition. Our results revealed the necessity for breast cancer cells to maintain free cholesterol levels at the expense of diminished cholesteryl esters through biosynthesis upregulation. Consequently, these LD-induced metabolic changes altered breast cancer cell sensitivity to treatments targeting the cholesterol pathway: While the LD condition increased cell sensitivity to cholesterol biosynthesis inhibition, this condition diminished sensitivity to cholesterol esterification inhibition. Therefore, in light of the growing prevalence of obesity-related dyslipidemia and the emergence of lipid-targeting antitumor therapies, our findings showcase the potential of targeting free cholesterol as a rate-limiting lipid in breast cancer growth. Importantly, these data prompt us to investigate how combined cholesterol-targeting drug therapies and dietary interventions may produce synergistic or antagonistic effects that are altered by systemic lipid dysregulation.