Life Extension Magazine December 2001
By Terri Mitchell
Mutated Hormones That Cause Cancer
Hormone-related cancers are on the rise. Prostate cancer rose 125% between 1973 and 1994. It now accounts for 14.8% of all new cancer cases, on the heels of breast cancer which leads the pack at 16.3% of all new cancer diagnoses. According to the National Cancer Institute, one out of every eight women will develop breast cancer in her lifetime. According to a 36-page analysis, the rate of all cancers rose 22% for women and 56% for men from 1975 to 1994, a generation that was most heavily exposed to the insecticide, DDT. In this article, we explain why our natural hormones mutate to form lethal compounds in the body. We also reveal what you can do to protect your precious DNA from these proven carcinogens.
Hormone-disrupting chemicals are prime suspects in the astronomical increase in breast, prostate and other cancers. Chemicals that mimic estrogen and/or disrupt other hormones include bisphenol-A which is used in plastic milk jugs and can linings; DDT and DDE which may be present on imported fruits and vegetables; phthalates found in plastic wrap-especially very clingy deli-wrap; and pesticides commonly used on lawns and gardens. This is the short list. The environment is so saturated with these hormone-disrupters, being exposed to them is all but inevitable. Given that it's difficult to escape them, is there anything that will neutralize their effects?
During the 1980s, it was reported in the New England Journal of Medicine that women who smoke 25 or more cigarettes a day cut their risk of endometrial cancer in half. This was a startling finding given what is known about the adverse health effects of smoking. Dr. Jon Michnovicz of Rockefeller University decided to look into it. Because of certain chemical properties of tobacco, Michnovicz theorized that smoking might be changing the way estrogen is metabolized. If that were the case, it would have the effect of lowering hormone-related cancers, and account for the conclusions of the NEJM study. In 1986 he published his own findings that heavy smoking did, in fact, change the way estrogen is metabolized by the body.*
The metabolic change that occurs is a change in hyroxylation. Hydroxylation is a biochemical process that chemically modifies a molecule to change how it behaves (cholesterol is turned into pregnenolone by hydroxylation, for example). Smoking shunts estrogen away from 16a-hydroxylation and towards 2-hydroxylation which creates a more benign estrogen. Having less 16a estrogen probably accounts for the reduced risk of endometrial and breast cancer in female smokers.
However, while smoking has beneficial effects on estrogen metabolism, it's not a great way to avoid cancer, so Dr. Michnovicz and others at Rockefeller began looking into other things that might force the body to, in a sense, detoxify estrogen. One of the things they looked at was cauliflower. Back in the 1970s, researchers at the University of Illinois reported that cauliflower and its cousins broccoli, Brussels sprouts, cabbage and mustard all contain a compound that can activate the enzyme necessary to convert estrogen to a less dangerous form. That compound is indole-3-carbinol, better known as I3C.
I3C is one of dozens of similar compounds created in the gut when cruciferous vegetables are digested. It most often makes the news because it's the most well-studied. But in addition to I3C there are N-methoxyindole-3-carbinol (NI3C), 3,3'-diindolymethane (DIM), indolo[3,2-b]carbazole (ICZ), indole-3-acetonitrile, ascorbigen and other anti-cancer compounds. All of these things come from a substance in cruciferous vegetables known as indole-3-glucosinolate. Indole-3-glucosinolate is one of many glucosinolates found in cruciferous vegetables. Each product of the glucosinolate (which is created naturally as the vegetable gets digested) has distinct characteristics. And it may act one way in one cell, and completely differently in another. For example, some of the compounds affect the estrogen receptor; others do not. But those others may work in a different way to change how estrogen interacts with the body. So it has been found, for example, that while indole-3-acetonitrile doesn't do a thing for breast cancer, it looks promising against stomach cancer.
There are dozens of indoles to investigate, but researchers are currently focused on I3C, DIM and ICZ because they have the most proof behind them as to being able to affect the underlying mechanisms of hormone-related cancers. You may have heard of sulforaphane. This is a different type of phytochemical which is also of interest to cancer researchers. Sulforaphane is found in high amounts in broccoli.
I3C has the most well-documented effects of all the glucosinolate products studied so far. Studies in humans show that I3C supplements increase the 2-hydroxylation of estrogen at the expense of other, more dangerous estrogens including 16a.
The question arises, then, that if I3C and other compounds can change the way our body's own estrogen behaves, could it do the same to estrogen-mimicking chemicals? What about chemical estrogens? Could I3C help us detoxify the estrogen-like chemicals in our milk jugs and plastic wrap? The answer is probably. While definitive proof is not available yet, preliminary studies indicate that I3C can detoxify fake estrogens the same way it does real estrogens.
DMBA is the chemical usually given to rodents to induce breast cancer for experiments. DMBA increases the 16a-hydroxylation metabolite-a dangerous estrogen. When I3C is given at the same time, less 16a-hydroxylation and less breast cancer occurs.
Dr. Leon Bradlow and his group at Rockefeller University have done studies on polychlorinated biphenyls (PCBs) and some pesticides including atrazine and DDT. They have been able to show that these estrogen-like chemicals also increase 16a-hydroxylation, just like DMBA. And just as I3C neutralizes the effects of DMBA, it neutralizes the effects of these chemicals as well.
As exciting as this research is, it doesn't translate into the notion that I3C can detoxify every hormone-mimicker that comes into the body. One of the major problems with studying the effects of hormone-disrupters on the human body is that humans ingest and breathe hundreds of chemicals. No one knows what they do in combination. While we know that I3C can detoxify some estrogen-mimickers, we don't know what effects it has on multiple chemicals, nor how much it would take to neutralize them. However, this only pertains to neutralizing estrogen. I3C has other completely different ways of blocking cancer.
Other mechanisms of I3C
When human breast cancer cells are treated with I3C in the test tube, 90% of them will stop growing. It doesn't matter whether they are estrogen receptor positive or negative. I3C stops their growth by mechanisms that don't rely on receptors.
When I3C is given to rodents before they are treated with cancer-causing chemicals, up to 90% of the cases of mammary cancer that would ordinarily develop don't develop. If I3C is given at the same time as cancer-causing chemicals, the number of tumors can be slashed by 96%. I3C also slashes the rate of naturally-occurring breast cancer in rodents by half.
One of the ways I3C protects cells against cancerous changes is by preventing DNA damage. Studies show that I3C is just short of amazing in its ability to protect DNA-not only in breast tissue, but in other tissues as well. A study from the Medical College of Ohio shows that I3C can cut the rate of DNA damage from chemicals in breast tissue by almost 92%. Others have shown that I3C decreases DNA damage in white blood cells by 82%, colon 67% and liver 69%. This would seem almost unbelievable if it hadn't been confirmed by others who have shown that I3C can reduce DMBA-induced liver adducts by 90%, lung and trachea by 55%, and other tissues by similar amounts.
I3C's potential as a chemopreventive agent was confirmed in a study funded by the National Cancer Institute where 90 different cancer preventatives were put through six different tests of cancer prevention. I3C was one of 8 compounds proven effective in all six assays (the other 7 were ascorbic acid, bismuththiol, esculetin, etoperidone, folic acid, hydrocortisone and tocopherol succinate).
Another potential action of I3C against chemical cancers is its potential to keep dioxin and other chlorine chemicals out of cells. Dioxin is so toxic it's measured in parts per trillion. (Other toxic chemicals are measured in parts per billion.) There is no known way to get dioxin out of the body except by breast-feeding. Losing weight will simply make it hunker down in the remaining fat.
Dioxin latches onto a receptor on cells known as the aryl hydrocarbon receptor (Ah receptor), where it gains access into cells. I3C can partially block that receptor and keep dioxin out. One of compounds that I3C naturally converts to in the body, ICZ, works even better. ICZ was found to be the best dioxin blocker found in a study of over 12 different compounds. Ironically, dioxin has the same beneficial effects on estrogen metabolism as I3C, but like cigarette smoke is not an ideal candidate for cancer prevention. In 1995, a national report was issued on the toxic effects of dioxin. It was 2000 pages long, published in six volumes.
It has been recently reported that I3C can affect cancer genes BRCA and Her-2/neu. BRCA normally functions as part of a DNA repair mechanism, and it also contributes to tumor suppression. BRCA is mutated (and nonfunctional) in many cases of familial breast, ovarian and prostate cancer. Researchers at Long Island Jewish Medical Center report that I3C can upregulate BRCA in breast cancer cells and prevent metastasis. It remains to be seen whether I3C would have any effect on people with BRCA mutations in their genes. However, it's interesting to note that the cell line used in the cell study was recently reported to have less BRCA action, indicating it probably has BRCA mutations. This means that I3C may have the potential to upregulate BRCA in people with a mutated gene.
HER-2/neu is an oncogene that is overexpressed in some cases of breast and cervical cancer. Herceptin is a chemotherapeutic drug developed to treat HER-positive cancers. Researchers at Wayne State University have been able to show that I3C can induce apoptosis (cell suicide) of HER-positive and -negative breast cancer cells.
Dozens of studies on I3C in humans and human cells indicate that it has multiple beneficial effects against hormone-related cancers. I3C is converted to several different products in the body, some of which haven't been studied yet, and while virtually nothing is known about them at this point, what is known about I3C is enough to say that this phytochemical has great promise against both the prevention and treatment of cancer. Perhaps the greatest testament to the powers of I3C is that drug companies are scrambling to make versions they can patent and sell as drugs.
Ambrosone CB, et al. 1996. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk [see comments]. JAMA 276(18):1494-501.
*The issue of whether smoking lowers the risk of breast cancer is not resolved. Any benefit, if any, is offset by the increased risk of lung cancer and lung metastases if the smoker does contract breast cancer.