LDL-cholesterol signaling induces breast cancer proliferation and invasion

Abstract

Lipids and cholesterol in particular, have long been associated with breast cancer (BC) onset and progression. However, the causative effects of elevated lipid levels and breast cancer remain largely undisclosed and were the subject of the present study.We took advantage of well-established in vitro and in vivo models of cholesterol enrichment to exploit the mechanism involved in LDL-cholesterol favouring BC growth and invasiveness. We analyzed its effects in models that mimic different BC subtypes and stages.Our data show that LDL-cholesterol (but not HDL-cholesterol) promotes BC cells proliferation, migration and loss of adhesion, hallmarks of the epithelial to mesenchymal transition. In vivo studies modeling cholesterol levels showed that breast tumors are consistently larger and more proliferative in hypercholesterolemic mice, which also have more frequently lung metastases. Microarray analysis revealed an over expression of intermediates of Akt and ERK pathways suggesting a survival response induced by LDL, confirmed by WB analyses. Gene expression analysis also evidenced an activation of ErbB2 signaling pathway and decreased expression of adhesion molecules (cadherin-related family member3, CD226, Claudin 7 and Ocludin) in the cells exposed to LDL.Together, the present work shows novel mechanistic evidence that high LDL-cholesterol levels promote BC progression. These data provide rationale for the clinical control of cholesterol levels in BC patients.

Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

“…Immune cell functions can thus be affected by alterations in cholesterol homeostasis (25). On the other hand, systemic cholesterol favors breast cancer progression by promoting breast cancer cell proliferation, migration and survival (30). LDL-cholesterol level in breast cancer patients has predictive value at the time of diagnosis: women with elevated LDLcholesterol levels at diagnosis have a higher risk of developing local recurrence or metastasis.…”

Identification of CETP as a molecular target for estrogen positive breast cancer cell death by cholesterol depleting agents

“…Interestingly the expression of oxysterol 7α-hydroxylase (CYP7B1), an enzyme which catabolises both 27HC and 25HC, is decreased in ER+ BC patient tissue and is predictive of overall poor survival [16, 40]. The cholesterol pathway constituents like LDL cholesterol, cholesterol receptors LDLR and SCARB1 and others have strong correlation with BC progression and clinical outcome [15, 21, 41–44]. These emerging data undeniably highlights the requirement for cholesterol modulating agents in BC management.…”

“…Dietary cholesterol [13] and particularly lipoproteins (both LDL and HDL) have been shown to fuel growth of breast tumours [20, 21], therefore a better understanding of cholesterol homeostasis for future BC therapeutics is necessary. The cholesteryl ester transfer protein (CETP) shuttles cholesteryl esters (CEs) and triglycerides between HDL and LDL to maintain cholesterol homeostasis both intracellularly and extracellularly [22].…”

Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

“…Low-density lipoproteins (LDLs) are the major carriers of cholesterol and have been studied mainly as cardiovascular risk factors but are increasingly recognized to play a role in cancer. LDLs promote proliferation, survival and migration of breast cancer cells (Nelson et al, 2013; dos Santos et al, 2014; Kitahara et al, 2011) and high LDL levels are associated with increased risk of prostate (Moses et al, 2009) and colorectal cancer (Holtzman et al, 1987). Statins lower LDL levels by blocking 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of cholesterol synthesis, and have anti-cancer properties (Mucci and Stampfer, 2014; Chae et al, 2014; Gronich and Rennert, 2013).…”