One of the most important strategies for treating women with estrogen-positive breast cancer is to block the action of estrogen. In estrogen positive (ER+) breast cancers, the natural estrogen in the body attaches to the estrogen receptors on cancer cells and stimulates them to divide, which makes breast tumors grow.
Once the initial treatment of breast cancer is completed, (surgery, chemotherapy, radiation), it is usually recommended that patients with ER+ tumors undergo long-term treatment with drugs like tamoxifen, which blocks estrogen activity, and aromatase inhibitors – Aromasin, Arimidex and Femara – which block the synthesis of estrogen in fat tissue in the body. These estrogen-blocking drugs work well for most women, but unfortunately, not all women respond to them, and it is not unusual for tumors to develop resistance to these drugs.
We are now learning more about why estrogen-blocking drugs may not work all the time, and one of the mechanisms comes from a surprising source: cholesterol! Like most molecules in the body, cholesterol gets metabolically transformed into other molecules by various enzymes in our body. One of the molecules that is derived from cholesterol, and which is present in fairly high levels in the body, is 27-hydroxycholesterol (27-HC). This interesting molecule can attach to and actually stimulate estrogen receptors in the body. Patients with ER+ breast cancer have higher amounts of 27-HC in the normal tissue in their breasts than women who have not been diagnosed with ER+ breast cancer. And the amount of 27-HC in breast tumors is even higher. This is because the enzyme that converts cholesterol to 27-HC is found in high levels in some breast cancer cells, especially in higher-grade tumors (higher grade tumors tend to grow rapidly and spread faster than lower grade tumors), and also in immune cells called macrophages, that sometimes infiltrate breast tumors.
In recent years, scientists have learned more about how 27-HC interacts with ER+ breast cancer cells. They have learned that it can stimulate the growth of ER+ breast cancer cells in the laboratory, both in the test tube and in mice. It can also cause breast cancer cells to change and become more prone to metastasis. In a paper published November 29 in the journal Science, investigators at Duke University in Durham, North Carolina, demonstrated that 27-HC increased both growth of ER+ tumors and metastasis of these tumors in mice. These effects could be stopped when the enzyme that makes 27-HC was blocked. These observations suggest that breast cancer cells have a way to get around the direct blocking of estrogen by drugs like tamoxifen or the aromatase inhibitors in order to grow: they can use 27-HC instead!
Rather than trying to develop a drug to block the enzyme that makes 27-HC, the Duke researchers presented a more practical idea for breast cancer patients. That is, they recommended they reduce their cholesterol levels either through diet or through the use of statin drugs. We know from a lab study that diet can increase the level of 27-HC: mice given a high fat/high cholesterol diet developed significantly higher levels of 27-HC, correlated with their levels of cholesterol (specifically, non-HDL cholesterol) and triglycerides. Several studies have also shown that breast cancer patients have higher levels of cholesterol than women who don’t have breast cancer.
We believe these findings make cholesterol levels a real target not only for breast cancer treatment, but also for breast cancer prevention. At the Block Center, our dietitians counsel our breast cancer patients who have elevated cholesterol levels on natural ways to lower their cholesterol. Though there is some epidemiological data suggesting that breast cancer patients who are taking statins are less likely to have disease progression, the laboratory data are probably not strong enough to persuade most physicians to immediately prescribe a statin to help them lower their cholesterol levels. However, naturally lowering cholesterol levels by diet modifications and the use of supplements may not only help keep levels of 27-HC in check, it may also improve cardiac risk factors. And, since research suggests that half of breast cancer patients actually die from cardiovascular disease, lowering elevated cholesterol levels via diet is a great choice for heart health as well!
- Keith Block