Even though scientists could not explain high cholesterol’s role in breast cancer, they suspected that a cholesterol-related mechanism of some sort was behind three key observations: first: high cholesterol is an independent risk factor for estrogen receptor (ER)-positive breast cancer in obese postmenopausal women; second, high cholesterol is associated with a decreased response of tumors to endocrine therapies; third, statins improve disease-free survival in breast cancer survivors who are taking statins before diagnosis.
If a cholesterol-related mechanism could be identified, scientists reasoned, it might not only explain a number of clinical observations, it might also present ways to lessen breast cancer risk. Such a mechanism has, in fact, been found, report researchers at the Duke University. In addition, say the researchers, the mechanism points to a straightforward strategy for preventing or treating breast cancer.
On the basis of work with mouse models and human breast cancer tissue, the researchers at Duke have found that a metabolite of cholesterol, 27-hydroxycholesterol (27HC), functions like the hormone estrogen to fuel the growth and spread of ER-positive breast cancers. Moreover, they found that statins appear to diminish the effect of 27HC.
These results were published November 29 in Science, in a paper entitled “27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology.” In this paper, the authors write that 27HC helped activate the ER and the liver X receptor (LXR) to increase “ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer.” The authors also note that the activity of 27HC was inhibited when animals were treated with anti-estrogens, or when supplementation of 27HC was stopped.
Providing more detail on the mechanism, the authors indicate that the effects of cholesterol on tumor pathology required its conversion to 27HC by an enzyme—the cytochrome P450 oxidase encoded by CYP27A1—and were attenuated by treatment with CYP27A1 inhibitors.”
The role of 27HC in tumor growth was studied yet further in experiments with human breast cancer tissue. This tissue showed a direct correlation between the aggressiveness of the tumor and the abundance of the cytochrome P450 oxidase. “The worse the tumors, the more they have of the enzyme,” said the study’s lead author Erik Nelson, Ph.D.
Evaluation of CYP27A1 expression levels revealed a potential association between 27HC exposure and the development of resistance to the anti-estrogen tamoxifen. Gene expression data also highlighted how increased 27HC may reduce the effectiveness of aromatase inhibitors, which are among the most commonly used breast cancer therapeutics.
“This is a very significant finding,” said senior author Donald McDonnell, Ph.D. “Human breast tumors, because they express this enzyme to make 27HC, are making an estrogen-like molecule that can promote the growth of the tumor. In essence, the tumors have developed a mechanism to use a different source of fuel.” This observation highlights a statement, made in the paper, that “in high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme.”
Dr. McDonnell said the findings suggest there may be a simple way to reduce the risk of breast cancer by keeping cholesterol in check, either with statins or a healthy diet. Additionally, for women who have breast cancer and high cholesterol, taking statins may delay or prevent resistance to endocrine therapies such as tamoxifen or aromatase inhibitors.