 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 a critical role 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 prolonged ingestion of a cholesterol-enriched diet induces a chronic auto-inflammatory response, 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 compound, 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 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 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% 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 will maybe get the best of both worlds. But what does that have to do with dietary cholesterol? I'm 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 may just be an 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 on 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%. I've explored before the role oxycholesterol 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 the 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 own 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 27Hc. 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, the enzyme that breaks down 27Hc 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 27Hc to grow when estrogen isn't available, and that may explain a second breast cancer mystery. Over 80% 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. 27Hc can fuel breast cancer growth without estrogen, which could explain why sometimes these estrogen blockers don't work. And finally, 27Hc may explain why breast cancer patients with higher vitamin D levels appear to live longer. Vitamin D supplementation decreases 27Hc 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 woman's breast cancer risk or slow tumor growth.