By CCSA Scientist: Dr. Amie Franklin
A relationship between obesity and breast cancer has long been observed, but researchers have struggled to identify the molecular underpinnings of this relationship. Now researchers have begun to connect the dots between obesity and breast cancer via the cholesterol breakdown product, 27-hydroxycholesterol (27HC). 27HC has been shown to function as a weak estrogen to support the growth of estrogen receptor-positive breast cancer cells grown in the lab and in mouse cancer models (original article here; also see more recent papers here and here). This research comes from the laboratories of Drs. Umetani and McDonnell. Donald McDonnell, PhD, chair of the Department of Pharmacology and Cancer Biology at Duke and Erik Nelson, Ph.D., have also discussed their research linking cholesterol to breast cancer on YouTube. This relationship is supported by recent results of a review of over one million patient records from the United Kingdom which identified a 1.64 times increased risk of breast cancer with increased cholesterol levels.
Though unexpected, this discovery makes sense based on molecular structure. Cholesterol is a precursor of estrogen (estradiol), thus 27HC shares its molecular structure with estrogen. However, the estrogen molecule has lost some of cholesterol’s molecular baggage to ensure that it binds to its own receptor and not the receptor for its close relative, testosterone. 27HC has been shown to bind about 150 times more weakly than estrogen to the estrogen receptor. However, this weak activity can partially be compensated by high levels of 27HC which occurs when cholesterol is high. Consequently, high levels of 27HC can activate the estrogen receptor even when estrogen levels are low, such as in post-menopausal women, women on aromatase inhibitors for breast cancer, and pre-menopausal women on ovarian suppression/removal for breast cancer. Considering that approximately 80% of breast cancers are estrogen-driven, reducing levels of cholesterol and, by proxy, 27HC, may reduce the risk of breast cancer. 27HC may even explain the development of tamoxifen-resistant, estrogen receptor-positive breast cancer.
Key takeaways:
- Obesity and high cholesterol are associated with elevated breast cancer risk.
- The cholesterol metabolite, 27-hydroxycholesterol (27HC), may be the link between obesity and breast cancer.
- Lab studies show 27HC can fuel estrogen-receptor positive breast cancer cells in tissue culture and in mouse cancer models.