Oxidized Cholesterol 27HC May Explain 3 Breast Cancer Mysteries

Michael Greger M.D. FACLM · January 16, 2019 · Volume 45

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Oxidized cholesterol (concentrated in products containing eggs, processed meat, and parmesan cheese) has cancer-fueling estrogenic effects on human breast cancer.

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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

In 1908, the presence of cholesterol crystals was noted “in the proliferating areas of cancers,” suggesting that perhaps cholesterol, in some way, was “associated with the regulation of [cancer] proliferation.” A century later, we now recognize “the accumulation of cholesterol [as] a general feature of cancer tissue, and recent evidence suggests that cholesterol [may indeed play] critical roles in the progression of cancers, including breast, prostate, and colorectal cancers.”

Perhaps that could explain why “egg consumption was associated with increased breast cancer risk.” And, indeed, a systematic review of the evidence suggests that “dietary cholesterol intake increases risk of breast cancer,” and the more cholesterol you eat, the higher the risk appears to go. But, why?

One thought is that the “[p]rolonged ingestion of a cholesterol-enriched diet induces chronic, auto-inflammatory responses,” and we know that “chronic…inflammation can lead to the initiation, promotion, and progression of tumor development.” It’s true that sprinkling some cholesterol on white blood cells in a test tube can trigger the release of inflammatory compounds, and LDL cholesterol can induce breast cancer proliferation and invasion. But again, that’s in vitro, where you can show that like breast cancer cells can migrate nearly twice as far within a day in a petri dish in the presence of LDL cholesterol. But what about in people?

Well, the level of LDL cholesterol in the blood of women diagnosed with breast cancer does appear to be “a predictive factor of breast tumor progression.” About two years after surgery/chemo/radiation, not one of the women in the lowest third of LDL cholesterol levels had a cancer recurrence. The same could not be said for women with higher cholesterol. We know cholesterol can cause inflammation in our artery walls; maybe it’s also playing an effect on breast cancer initiation and progression? They speculate that the high cholesterol levels may have a “cancer-fueling effect.” And indeed, women with breast cancer who happen to be taking cholesterol-lowering statin drugs appear to live about 40 percent longer before the cancer comes back. But the data isn’t good enough to ensure the drug benefits outweigh the risks, though lowering cholesterol with diet, one may be able to get the best of both worlds. But what does this have to do with dietary cholesterol?

Sure, animal studies show that if you feed mice cholesterol, you can accelerate their cancers, “but extrapolation to humans is difficult as dietary cholesterol has limited effects on blood cholesterol levels in humans.” Thus, “dietary cholesterol might [just] be indicative of a lifestyle prone to health-related problems, including cancer.” Maybe people are just more likely to chase bacon and eggs down with a cigarette, compared to oatmeal? It’s hard to imagine how dietary cholesterol alone could promote cancer development. But that all changed recently, with the discovery that 27-Hydroxycholesterol, a metabolite of cholesterol, “can function as an estrogen and increase the proliferation” of most breast cancer cells.

Ah, so it’s not the cholesterol itself, but what it turns into in the body. “Scientists have long struggled to understand why women with heart disease risk factors are more likely to develop breast cancer.” Now, perhaps we know. “The discovery that the most abundant oxidized cholesterol metabolite” in our bloodstream can have estrogenic effects may explain the link between high cholesterol and the development and progression of breast cancer and prostate cancer. Yes, 27-Hydroxycholesterol also stimulates the proliferation of prostate cancer cells, boosting growth by about 50 percent.

I’ve explored before the role oxycholesterols may play in mediating pro-oxidative and pro-inflammatory processes in degenerative diseases, such as Alzheimer’s and heart disease, but now it looks like oxidized cholesterol can play a role in all three stages of tumor development as well: initiation, promotion, and then the progression of cancer. Not just promoting the growth of breast cancer cells, but also inducing their invasion and migration—potentially facilitating breast cancer metastasis through suppressing anti-cancer immunity, and then inducing angiogenesis, helping breast tumors hook up their blood supply.

This is all supported by “several lines of evidence [that point to] a pathologic role” for this cholesterol metabolite. Yeah, you can feed mice cholesterol; their oxysterol levels go up and their tumors accelerate. It “also appears to dramatically hasten the spread, or metastasis, of breast tumors to other organs.” But turning to human breast tissue samples, they found that more aggressive tumors have higher levels of the enzyme that converts cholesterol into 27-HC. In breast cancer patients with estrogen receptor-positive tumors, the 27 Hydroxycholesterol content in their breast tissue is increased overall, and especially within the tumor itself—so much so that circulating oxysterol levels in the blood may one day be used as a prognostic factor. And “breast cancer patients with low tumor levels of [the enzyme] that breaks down 27-HC did not live as long” as women who can detoxify it better. “The bottom line…is that some estrogen-driven breast tumors may rely on 27-HC to grow when estrogen isn’t available.” And that may explain a second breast cancer mystery.

Over 80 percent of breast cancers start out responding to estrogen, and so what we do is use hormone blockers—either aromatase inhibitors to stop the formation of estrogen in the first place, or tamoxifen to block its action. Despite the efficacy of these drugs, many patients relapse with resistant tumors. And that’s where oxidized cholesterol can come in. 27-HC can fuel breast cancer growth without estrogen, which could explain why sometimes these estrogen blockers don’t work.

And finally, 27-HC may explain why breast cancer patients with higher vitamin D levels appear to live longer. Vitamin D supplementation decreases 27-HC levels in the blood. The best way, though, may be to just lower overall cholesterol. Lower cholesterol, and you lower oxidized cholesterol. So, discovering this role of cholesterol is actually really good news, since “cholesterol is a highly amenable risk factor, either by lifestyle, dietary, or pharmacologic interventions.” The implications of these findings, according to the principal investigator, is that “lowering cholesterol with dietary changes or [drugs] could reduce a women’s breast cancer risk or slow tumor growth.”

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Image credit: Ed Uthman via flickr. Image has been modified.

Motion graphics by Avocado Video

Doctor's Note

The video I mentioned is How to Reduce Cholesterol Oxidation. For the role in Alzheimer’s disease, see Oxidized Cholesterol as a Cause of Alzheimer’s Disease.

This is the third in a three-part video series on cholesterol and cancer. In case you missed the first two: Eggs & Breast Cancer and Dietary Cholesterol & Cancer.

There are all sorts of foods that can decrease breast cancer risk, though, and even improve survival. See, for example:

Best way to get D? See The Best Way to Get Vitamin D: Sun, Supplements, or Salons? and The Risks & Benefits of Sensible Sun Exposure.

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