Review
Cholesterol and breast cancer pathophysiology

https://doi.org/10.1016/j.tem.2014.10.001Get rights and content

Highlights

  • Elevated cholesterol is associated with breast cancer risk.

  • Cholesterol promotes breast tumor growth and metastasis in murine models.

  • A cholesterol metabolite acts as an estrogen receptor agonist to promote tumor growth.

  • Novel strategies to target cholesterol/oxysterol metabolism.

Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in increased cholesterol content in cell membranes, thus impacting upon membrane fluidity and subsequent signaling. In addition, studies demonstrate that the metabolite, 27-hydroxycholesterol (27HC), can function as an estrogen, increasing the proliferation of estrogen receptor (ER)-positive breast cancer cells. This was unexpected because 27HC and other oxysterols activate the liver X receptors (LXR), resulting in a reduction of intracellular cholesterol. Resolution of this paradox will require dissection of the molecular mechanisms by which ER and LXR converge in breast cancer cells. Regardless, the observation that 27HC influences breast cancer provides a rationale for strategies that target cholesterol metabolism.

Section snippets

Breast cancer risk factors

Breast cancer continues to be the most commonly diagnosed cancer in women, and is the second highest cause of cancer deaths [1]. Thus, notwithstanding the importance of developing new and effective therapeutics, there is significant interest in defining breast cancer risk factors and exploiting this information to develop chemopreventative and lifestyle modification strategies that can help to reduce the burden of this disease. Among the best-studied risk factors for breast cancer are loss of

Cholesterol as a breast cancer risk factor

One of the first observations linking cholesterol and cancer was made in 1909 in a study which noted the presence of crystals of a ‘fatty nature’ in tumor sections prepared without alcohol fixation [11]. However, over 100 years later the cause and effect relationships between cholesterol and increased cancer risk remain unclear. This issue has been addressed in a large number of retrospective clinical studies, although these have yielded equivocal results, with many finding no relationship,

Cholesterol is implicated as a breast cancer risk factor in animal models

It was first noted in the early 1950s that obesity and elevated total cholesterol increase tumor incidence in mouse models of breast cancer [24]. More recently, however, it was shown that a high-fat, high-cholesterol (HFHC, Western) diet decreases the latency and increases the growth and metastasis of tumors in the murine MMTV-PyMT model of mammary cancer [25]. MMTV-PyMT mice are transgenic for the viral polyoma middle-T antigen under the control of the mouse mammary tumor virus (MMTV)

Mechanisms underlying the pathological actions of cholesterol in breast cancer

Free cholesterol in most cells is maintained at a very constant level by a series of homeostatic processes that regulate: (i) partitioning into the plasma and endoplasmic membranes; (ii) efflux, uptake, and de novo synthesis; and (ii) esterification by acyl-CoA:cholesterol acyltransferase (ACAT) [33]. One of the key regulators of intracellular cholesterol levels is sterol regulatory element binding protein-2 (SREBP2), a transcription factor that functions as a sensor for cholesterol and whose

27HC and breast cancer

The synthesis of 27HC from cholesterol is catalyzed by the enzyme CYP27A1 in what is known as the ‘alternative’ or ‘acidic’ pathway for bile acid synthesis. It has been observed, both in humans and in animals, that the circulating levels of 27HC closely mirror those of cholesterol, and that hypercholesterolemia results in commensurately high levels of 27HC [47]. It has also been demonstrated that 27HC is an LXR agonist and as such serves to limit cholesterol accumulation in cells 45, 48, 49.

27HC as an autocrine/paracrine modulator of tumor growth

It is clear that the circulating levels of 27HC mirror those of cholesterol, suggesting that strategies to lower cholesterol will have a commensurate effect on 27HC [47]. However, it has also become apparent that the development of approaches to mitigate the impact of 27HC on tumor pathogenesis will also need to address how best to reduce local production of this oxysterol. It is likely that the majority of circulating 27HC is derived from the liver, a tissue where CYP27A1 is highly expressed.

Linking obesity, HFD, 27HC, and cancer biology

As mentioned, obesity is a risk factor for several types of cancer, and this association is particularly apparent when looking at the incidence of ER-positive breast cancers in post-menopausal women 4, 5. While several biochemical mechanisms have been identified that link obesity and breast cancer [6], the specific contribution of cholesterol, a comorbidity of obesity, in cancer pathogenesis has been underappreciated. We believe that this may be due in part to the fact that mice do not exhibit

27HC and breast cancer metastasis

Several epidemiological studies have identified a positive association between either obesity or cholesterol and breast cancer metastases (relapse-free survival) 60, 61. Based on the ability of 27HC to activate the ER and promote tumor growth, an obvious hypothesis is that the effects of cholesterol on metastasis were mediated in a similar manner. However, when investigating the effects of 27HC on metastasis it was determined that the ER ligand, 17β-estradiol, did not increase the metastatic

Concluding remarks and future perspectives

In addition to increased insulin, IGFs, adipokines, and local production of estrogens, there is clear evidence to support an independent role for cholesterol as a mediator of the effects of dyslipidemia and/or obesity on breast cancer pathogenesis. One major mechanism by which cholesterol imparts its effects on breast cancer is via its metabolite, 27HC, a molecule with SERM activity. Of the oxysterols, 27HC circulates at the highest concentrations. However, it has been shown that other

Acknowledgments

This work was supported by Department of Defense Idea Expansion Award W81XWH-13-1-0366 (to D.P.M.), National Cancer Institute of the National Institutes of Health K99CA172357 (to E.R.N.), and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health R37DK048807 (to D.P.M.).

Glossary

Apolipoprotein E
a protein involved in the transport of lipoproteins and cholesterol in the blood and lymphatic systems. In mice there is only one allele (Apoe). In humans, the most common allele is APOE3. Unlike wild type mice, mice lacking APOE or transgenic for human APOE3 develop hypercholesterolemia when fed a high-fat normal-cholesterol diet.
ATP-binding cassette subfamily A1 (ABCA1) and ABCG1
proteins involved in the reverse transport of cholesterol.
CYP27A1
cytochrome P450, family 27,

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