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Hypercholesterolemia May Drive the Growth of Breast Cancer

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Key Points

  • Elevated levels of 27-hydroxycholesterol may drive the growth of breast cancer, according to recent preclinical study findings.
  • Increased metastasis of breast cancer cells to the lungs may be associated with elevated levels of circulating 27-hydroxycholesterol in animal models.
  • Lowering total cholesterol levels may result in a reduction in breast cancer risk and possibly may affect a woman’s response to endocrine therapy.

High levels of the cholesterol metabolite 27-hydroxycholesterol seem to function like estrogen and may independently drive the growth of breast cancer, according to the findings of a preclinical study by Nelson et al published in Science. They also found a possible connection between 27-hydroxycholesterol exposure and the development of resistance to antiestrogens. This link between hypercholesterolemia and breast cancer suggests that lowering total cholesterol levels may become a useful strategy for reducing the risk of breast cancer.

Direct Involvement in Tumor Growth

The investigators evaluated the impact of 27-hydroxycholesterol on tumor pathophysiology using mouse models and human breast cancer tissue. They also attempted to determine whether the estrogenic activity of 27-hydroxycholesterol on its own could promote the growth and metastasis of breast tumors in mice.

In the mouse models of estrogen receptor?positive breast cancer, the tumor-promoting effects of 27-hydroxycholesterol were confirmed. Not only was this cholesterol metabolite directly involved in breast tumor growth, it also was linked to its metastatic potential, with increased metastasis of breast cancer cells to the lungs noted in mice with elevated levels of circulating 27-hydroxycholesterol. Moreover, tumor metastasis was increased by activation of liver X receptor by 27-hydroxycholesterol, and the investigators noted that these activities occurred independently of estrogen receptors.

The investigators demonstrated that tumor growth was increased by either 17β-estradiol or 27-hydroxycholesterol supplementation. Furthermore, the activity of this molecule was inhibited by co-treatment with an antiestrogen or cessation of 27-hydroxycholesterol supplementation.

Other Preliminary Findings

Other findings of interest from this preliminary stage of research focused on outcomes in estrogen receptor?positive tumors and dietary implications. The investigators found that overexpression of CYP7B1 mRNA was associated with better survival outcomes in luminal A types of tumors, whereas expression of CYP27A1 (the cytochrome P450 oxidase needed to convert cholesterol to 27-hydroxycholesterol) mRNA did not correlate with outcomes in estrogen receptor?positive tumors. The authors emphasized the importance of this finding, noting that luminal A breast tumors generally express estrogen receptors, would be expected to be influenced by the estrogenic activity of 27-hydroxycholesterol, and are most likely to respond to estrogen receptor antagonists or aromatase inhibitors.

In regard to dietary implications, the investigators confirmed that in mice fed a high-cholesterol diet, intratumoral concentrations of 27-hydroxycholesterol were increased. However, in mice with undetectable levels of 27-hydroxycholesterol fed a control diet, there was an increase in tumor latency and a decrease in tumor growth. Furthermore, circulating levels of both total cholesterol and 27-hydroxycholesterol in mice fed a high-fat diet were significantly increased, and the tumors grew faster in these mice than in those on a control diet.

Clinical Implications

Hypercholesterolemia has been identified as an independent risk factor for breast cancer in postmenopausal women, and these results from Nelson et al may have clinical implications for the future treatment and prevention of breast cancer. Their data suggest that lowering total cholesterol levels may result in a reduction in breast cancer risk and possibly may affect a woman’s response to endocrine therapy. Clinical studies to verify these early findings are warranted, the investigators added, as well as to determine whether 27-hydroxycholesterol may play a role in the growth of other cancers.

In closing, the investigators stated, “In this APOE3 mouse model, a high-fat diet enhances tumor growth, an effect that can be partially reversed by treatment with agents that inhibit the biosynthesis of cholesterol or 27-hydroxycholesterol.”

Donald P. McDonnell, PhD, of Duke University School of Medicine, is the corresponding author of the article in Science.

This study was funded by the National Institutes of Health and the Department of Defense.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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