HDL and LDL: Potential New Players in Breast Cancer Development

Abstract

Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the progress to date in research on the potential role of the main cholesterol transporters, low-density and high-density lipoproteins (LDL and HDL), on breast cancer development. Although some studies have failed to find associations between lipoproteins and breast cancer, some large clinical studies have demonstrated a direct association between LDL cholesterol levels and breast cancer risk and an inverse association between HDL cholesterol and breast cancer risk. Research in breast cancer cells and experimental mouse models of breast cancer have demonstrated an important role for cholesterol and its transporters in breast cancer development. Instead of cholesterol, the cholesterol metabolite 27-hydroxycholesterol induces the proliferation of estrogen receptor-positive breast cancer cells and facilitates metastasis. Oxidative modification of the lipoproteins and HDL glycation activate different inflammation-related pathways, thereby enhancing cell proliferation and migration and inhibiting apoptosis. Cholesterol-lowering drugs and apolipoprotein A-I mimetics have emerged as potential therapeutic agents to prevent the deleterious effects of high cholesterol in breast cancer.

Keywords: 27-hydroxycholesterol; Breast cancer; HDL; LDL; cholesterol; cholesterol-lowering therapies.

Figure 1

Effects of human apolipoprotein A-II (hApoA-II) overexpression on tumor development in polyoma middle T (PyMT) mice. PyMT mice were backcrossed with hApoA-II transgenic (TG) mice on a C57BL/6 background. The mice were maintained on a regular chow diet until 19 weeks of age, when they were euthanized, and the mammary glands were excised and weighed. Serum lipids were determined after an overnight fasting period and 3 h after a 0.15 mL dose of olive oil by oral gavage. A) Mammary gland weight. B) Serum lipid levels in fasting and postprandial conditions (TG = triglycerides, and HDL-C = high-density lipoprotein cholesterol). Values shown represent the mean ± SEM. A t-test was performed to determine the statistical significance between groups. * p < 0.05 vs. PyMT mice.

Figure 2

Mechanisms by which low-density lipoprotein (LDL), high-density lipoprotein (HDL), and their modified forms induce proliferation and migration and reduce apoptosis in breast cancer cells. OLR1 = OxLDL lecithin-like receptor 1, LDLR = LDL receptor, SR-BI = scavenger receptor class B type I, HMGCR = hydroxy-methyl-glutaryl-coenzyme A reductase, ACAT1 = acyl-CoA:cholesterol acyltransferase 1, 27-HC = 27-hydroxycholesterol, ERK1/2 = extracellular signal-regulated kinases ½, NFκB = nuclear factor κB, and ER/LXR = estrogen receptor/liver X receptor.