27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology

Abstract

Hypercholesterolemia is a risk factor for estrogen receptor (ER) positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here we show that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and Liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1, and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.

High-Density Lipoprotein-Cholesterol, Daily Estradiol and Progesterone, and Mammographic Density Phenotypes in Premenopausal Women

“…Low levels of HDL-C have been observed to induce higher levels of proinflammatory cytokines (6), and proinflammatory cytokines were recently found to induce higher local estradiol levels and cellular proliferation in the breast (44,45), and to be associatied with percent mammographic density (46). Furthermore, hypercholesterolemia, strongly associated with low HDL-C, may induce angiogenesis (47), and accelerating breast cell growth and metastasis (8,9).…”

“…Low levels of HDL-C, which transport and store cholesterol (4), have been associated with low-grade inflammation and proinflammatory cytokines (5-7), which may stimulate breast cell proliferation. High levels of the cholesterol metabolite 27-hydroxycholesterol were observed to increase estrogen-dependent breast cancer proliferation (8,9). Interestingly, mammographic density, a strong predictor of breast cancer development, is positively correlated with the number of epithelial cells (10), and mammographic density was recently linked to metabolic syndrome (11).…”

Cholesterol lowering: role in cancer prevention and treatment

“…Dietary cholesterol intake is positively associated with the risk of breast cancer (Hu et al, 2012), and oxysterol 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol (Figure 2A), increases tumor growth and metastasis in mouse models of breast cancer (Nelson et al, 2013). Furthermore, cholesterol is a precursor of estrogen, and high estrogen levels are associated with an increased risk of breast cancer (Yager and Davidson, 2006) (Figure 2A).…”

Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer

“…Despite the substantial amount of preclinical evidence supporting a role for 27HC in breast cancer pathobiology (Nelson et al 2013), it remains to be determined if variability in serum and/or intratumoral levels of 27HC or of CYP27A1 influences clinical breast cancer tumor pathology and patient outcome. The circulating levels of 27HC and cholesterol have been reported to be significantly positively correlated, and plasma 27HC tends to be elevated with hypercholesterolemia and increasing age (Brown & Jessup 1999, Burkard et al 2007, Wu et al 2013.…”

“…As such, it was not surprising that 27HC was shown to increase breast cancer growth and metastatic progression in preclinical experimental models and that this activity was attenuated by genetic and pharmacological approaches (i.e. inhibition of either 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)) that interfered with the production of cholesterol and/or the conversion of cholesterol to 27HC (Nelson et al 2013, Wu et al 2013. Thus, although the hydroxylation of cholesterol catalyzed by CYP27A1 is a mechanism utilized by cells to eliminate cholesterol from peripheral tissues, it can also result in the production of an ER ligand that likely contributes to breast cancer pathogenesis.…”