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Increased Breast Cancer Risk: Another implication of high cholesterol
James Meschino DC, MS, ROHP
In addition to being a known risk factor for heart and cardiovascular disease recent studies have highlighted the link between high cholesterol and increased risk of breast cancer. Breast cancer is the second most common malignancy in women after skin cancer. The majority of breast cancer is influenced by the stimulatory effect of estrogen on alpha-estrogen receptors on breast cells, which up-regulates their proliferation rate and the risk of estrogen receptor-positive (ER+) breast cancer (which is greatest in postmenopausal women).
Until recently estrogen has been the only known endogenous estrogen receptor ligand (binding agent) that promotes ER+ breast tumor growth. However, new discoveries show the cholesterol metabolite 27-hydroxycholesterol (27HC) binds to alpha-estrogen receptors and up-regulates the rate of breast cell and breast cancer cell division. In experimental studies 27HC has been shown to stimulate breast cancer growth in mice with transplanted estrogen receptor-positive breast cells from humans. Human studies show that in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to cancer-free controls, and that tumor 27HC abundance is further elevated.Increases in tumor 27HC are shown to be related to diminished expression of the 27HC metabolizing enzyme CYP7B1, which accompanies menopause.
Postmenopausal Obesity, High Fat Diet and High Cholesterol: The perfect breast cancer risk factor storm
It is well documented that over weight postmenopausal women have a three-fold increase in breast cancer risk. This has been linked to higher estrogen synthesis and secretion from fat cells, which in turn over stimulate the cell division rate of breast cells, and impose other changes conducive to the development of breast cancer. In addition, it is also well established that hypercholesterolemia is a risk factor for estrogen receptor-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies.Evidence is mounting that the form of cholesterol that is most dangerous to the development of breast cancer is 27HC.
There are three common situations whereby 27HC is typically elevated. The first is during the postmenopausal period. Serum 27HC levels increase in women after menopause, which appears to be caused by estrogen deprivation, as mice studies show that beta-estradiol upregulates hepatic CYP7B1 expression. CYP7B1 is the enzyme that detoxifies 27HC in the liver. Thus, the rate of 27HC detoxification declines after menopause due largely to the age-related decline in estrogen that accompanies menopause. At the same time the synthesis of 27HC from cholesterol continues at the normal pace, which is dependent on the enzyme CYP27A1. Thus, the decline in estrogen during menopause tends to increase circulating 27HC levels, which is exacerbated when blood cholesterol is high. As such, 27HC is shown to be higher in women with hypercholesterolemia and with obesity, which is frequently associated with hypercholesterolemia.
In mice, a high-fat, high-cholesterol western diet elevates serum 27HC by 2- to 3-fold. In women, both dyslipidemia and obesity raise breast cancer risk and severity, with obesity particularly having an adverse impact in postmenopausal women and breast cancer promotion, especially in regard to estrogen receptor-positive breast cancer (1).
Of note is the further observation that“ the enzyme responsible for the conversion of cholesterol to 27HC (CYP27A1) is primarily expressed in macrophages. And because tumor infiltrating macrophages are associated with more aggressive tumors and worse patient outcome, data suggests that 27HC, acting as either a circulating hormone or as a paracrine factor produced by macrophages, is a mechanistic link between hypercholesterolemia and breast cancer incidence”. (2)
In one study researchers noted that “the most aggressive human breast cancers were found to express the highest level of the enzyme that converts cholesterol to 27HC, the researchers conclude that 27HC produced within tumors – in addition to circulating 27HC – may contribute to tumorigenesis, spurring the growth and spread of the most common breast cancer in mice, and perhaps in some women”. (2)
Some MD’s Now Recommend Statin Drugs to Reduce Breast Cancer Risk
Some preliminary studies have found that patients taking anti-cholesterol statin drugs, which inhibit cholesterol production, demonstrate lower breast cancer incidence, and decreased breast cancer recurrence.(2) This makes sense given the fact that high cholesterol levels tend raise 27HC levels, which is becoming highly incriminated in breast cancer development and progression. The flipside of the statin drug story is that the use of statin drugs is known to increase risk of liver damage, can trigger or aggravate diabetic states, increase risk of memory loss and induce joint pain. In very rare cases it can cause life-threatening rhabdomyolysis (3, 4)
Given these facts, there are other ways to keep cholesterol in the ideal range (below 3.9 mmol/L; 150 mg/dL) for more than 90% of the population who are not genetically predisposed to high cholesterol problems. With respect to attaining ideal cholesterol values health practitioners who emphasize natural approaches to health managements should discuss the importance diet, exercise and targeted natural supplements that have been shown to reduce cholesterol. These natural approaches do not impose the side effects associated with statin drugs, and therefore, unless dealing with a patient who is at high-risk for a cardiovascular disease event (or genetically-induced high cholesterol), health practitioners should interest their patients in natural, safe approaches to the management of obesity and high cholesterol as much as possible. The payoff is appears to be not only reduced risk of cardiovascular disease, but also reduced risk of breast cancer, according to recent data. This natural approach is often over looked in the conventional management of high cholesterol, as doctors often focus their attention almost exclusively on the role of statin drugs. Some of the natural strategies to lower cholesterol can be found by accessing my previous published articles on this subject, including the following:
- Wu Q, Ishikawa T,Siriannin R, Tang H, McDonald JG et al.27-Hydroxycholesterol Promotes Cell-Autonomous, ER-Positive Breast Cancer Growth. Cell Reports, Volume 5, Issue 3, 637-645, 07 November 2013