The Gene Connection In Preventing
Estrogen-Related Cancers

New Information on How Certain Compounds
in Cruciferous Vegetables Modify Gene Activity

Many of the vital decisions in our lives have to do with optimizing certain ratios: the ratio of income to expenditures, for example, or of calories consumed to calories burned, or of time spent working to time spent playing. (Coco Chanel once said, "There is time for work. And time for love. That leaves no other time.") It's a sure bet, however, that most people don't spend much effort trying to optimize their ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone. (Huh?) That's a pity, because their lives may depend on it - literally.

The chemical compounds 2-hydroxyestrone and 16-alpha-hydroxyestrone are estrogen metabolites - substances resulting from metabolic processes involving estrogen. Estrogen is the collective term for several of the female sex hormones (principally estrone, estradiol, and estriol), and metabolism is the complex physical and chemical processes occurring within a living cell or organism that are necessary for the maintenance of life.

Readers of this magazine may recall that 2-hydroxyestrone is a "good" molecule and 16-alpha-hydroxyestrone is a "bad" molecule, and that a high ratio of the good molecule to the bad molecule is associated with a reduced risk for estrogen-related cancers, notably those of the breast and the female reproductive organs. Conversely, a low ratio is associated with an increased risk for these cancers. (For a refresher on this subject, see the articles "Defeating Out-of-Control Cell Growth" and "Achieving a Healthy Sex-Hormone Ratio" in the September and October 2000 issues, respectively, of Life Enhancement.)

ATTENTION, MEN
Men, if you've gotten this far but are thinking, "Estrogen-enhanced cancer couldn't apply to me, because I'm a guy, and guys don't have estrogen," think again. All men have some estrogen in their systems, and the older they get, the more of it they have, relative to the male hormone testosterone. This does not mean that if you live long enough you'll turn into a woman, but it can still cause serious problems. Excessive conversion of testosterone to estrogen (the male and female sex hormones are close chemical relatives) is not uncommon in aging men, and this is believed to be associated with a wide range of cellular abnormalities, including prostate cancer. It is also linked to a higher risk for heart disease.

So, this article is for you men, as well as for women - especially if you're interested in a new, genetic perspective on the benefits of certain nutritional supplements in helping to prevent cancer. The new research illustrates how we may be able to modify the activity of certain of our genes to our advantage. Before we get to the genes in question, however, let's have a look at those supplements.

CRUCIFEROUS VEGETABLES HELP PREVENT CANCER
All of us have heard from time to time that broccoli is particularly good for us because it has anticancer properties. It's true. Broccoli, as well as the other so-called cruciferous vegetables, of the genus Brassica - cabbage,cauliflower, bok choy, Brussels sprouts, kale, kohlrabi, rutabaga, turnip,and mustard - contains chemical compounds that have been shown to inhibit abnormal cell proliferation, the hallmark of cancer.

One of these compounds is indole-3-carbinol (called I3C for short), which in both laboratory and clinical studies has been found to be a potent inhibitor of estrogen-related cancers. We should all probably be getting more of it than we do. Actually, I3C does not exist as such in the fresh vegetables. It is produced naturally from parent compounds called glucobrassicins when the vegetables are processed by chopping or shredding or juicing (or, ultimately, chewing). Such actions disrupt the cell walls, and this initiates the chemical reactions leading to I3C.


Figure 1. The processes by which I3C and its
derivatives ascorbigen and DIM are formed.

What happens next is interesting and somewhat surprising (see Figure 1). When I3C is created, some of it reacts with the ascorbic acid (vitamin C) in the vegetable to form a compound called ascorbigen, which is believed to be an even better anticancer agent than I3C. And when I3C is swallowed and reaches the highly acidic environment of the stomach, much of it is converted to yet another potent anticancer agent called 3,3'-diindolylmethane, or DIM for short; DIM is formed when two I3C molecules are joined by achemical bond.

REDUCING ESTROGENIC ACTIVITY IS THE KEY
What all three of these compounds - I3C, DIM, and ascorbigen - have in common is their ability to improve the molecular ratio we mentioned earlier. But how does that result in a decreased risk of cancer? How do those molecules exert their good or bad effects? It is through their estrogenic activity - the degree to which they mimic the effects of estrogen. As we have seen, one of the cruel paradoxes of human physiology is that the female sex hormones, which so clearly define a woman's being (just as testosterone defines a man's), can play a role in hastening her demise by inducing breast cancer or cancers of the reproductive organs, such as the ovaries and the endometrium (the lining of the uterus).

Researchers believe that the greater a woman's exposure to estrogen, the more susceptible she becomes to cancer. A basic function of estrogen is to tell cells to divide. The more they divide (proliferate), the more likely it is that some of them will be abnormal in some way - possibly in a way that turns malignant.

Thus, although a certain amount of estrogen is vital for women, even with advancing years - particularly for its important role in reducing the risk of heart disease and osteoporosis (brittle bones) - too much of it can be harmful.

REDUCING ESTROGENIC ACTIVITY CAN ALSO HELP PREVENT PROSTATE CANCER
Too much estrogen can also be harmful for men, particularly in terms of prostate cancer, which is the second most common cause of cancer death (after lung cancer and before colorectal cancer) in men. Prostate cancer is extremely common; half of all men over the age of 70 have it, and virtually all men over 90 have it. Unfortunately, most prostate cancers cause few or no symptoms, because they grow and spread slowly, but some do grow aggressively and spread throughout the body. In addition to the basic requirements of a good diet, regular exercise, and no smoking, one way to decrease the risk of prostate cancer is to suppress estrogenic activity.


When I3C binds to the protein
surface of the estrogen receptor,
its activity is suppressed, thereby
helping to prevent prostate cancer.

I3C SEEKS OUT CERTAIN GENES
In a study published last year in the Journal of Nutrition, the objective was to investigate the ability of I3C to suppress estrogenic activity by inhibiting the action of a certain estrogen receptor (called ER-alpha) in laboratory experiments.1 Estrogen receptors are specialized molecules found in all cells of the body. As the name implies, they have a chemical affinity for estrogen molecules (which are much smaller and can diffuse freely into all cells). The molecular structures of different estrogen receptors allow them to bind chemically to the specific estrogen molecules for which nature designed them.

When this occurs, the resulting molecular complexes migrate to the cell's DNA, where they seek out certain genes. A gene is a particular, well-defined segment of a DNA molecule, and every gene is unique in its chemical composition. For most genes, the details of this composition constitute coded information that governs the synthesis of a protein. Thus, a given gene codes for one specific protein, and no other.

When the estrogen/estrogen receptor complexes have found their "target" genes, they instruct them (through chemical reactions) to initiate the process of protein synthesis. This is called a signaling mechanism. Some of the proteins produced are beneficial, but some are harmful, tending to promote cancer. It is the harmful ones that are of concern to medical scientists.

I3C SUPPRESSES BAD GENE ACTIVITY AND AMPLIFIES THE GOOD
In their experiments, the researchers found that when estradiol was the estrogen used, I3C significantly suppressed the signaling mechanism of ER-alpha. This occurred in a dose-dependent manner: the more I3C there was, the greater the suppression. The researchers were able to show that, by suppressing the signaling mechanism, I3C makes certain potentially harmful genes less active, which means that the production of their proteins is curtailed.

The same research group had previously shown that I3C makes a certain beneficial gene more active. This gene, called BRCA1 (for the breast cancer susceptibility gene 1) possesses multiple biological functions as a tumor suppressor.2,3 It codes for a protein called BRCA1 (note the typographic distinction to help tell the gene from its protein), and it turns out that BRCA1, like I3C, also suppresses the signaling mechanism of ER-alpha.4 The effects of the I3C and BRCA1 molecules are synergistic, i.e., the combined effect is greater than the sum of the individual effects.

I3C HAS ANTIESTROGENIC AND OTHER ANTITUMOR ACTIVITIES
Alluding to the biological importance of the BRCA1 gene, the authors state that mutations (changes caused by outside factors) in this gene increase the risk of breast and ovarian cancer, as well as the risk of prostate cancer in men. Their study and previous ones have shown that exposure of cells to I3C significantly amplifies the action of BRCA1, which is to say that it increases the production of BRCA1. They go on to say that the ability of I3C to do this, together with the synergistic effect of these two substances in suppressing the signaling mechanism of ER-alpha, increases the overall effectiveness of I3C as an anticancer agent.

The authors also mention I3C's known ability to affect estrogen metabolism by optimizing the ratio of 2-hydroxyestrone (whose low estrogenic activity is beneficial) to 16-alpha-hydroxyestrone (whose high estrogenic activity is harmful). In the context of their own gene-related research, this led them to state that I3C thus appears to reduce estrogenic activity by multiple mechanisms. They further state, "In addition to the powerful effect of antiestrogenic activities, I3C has other antitumor activities. . . . Together, these beneficial effects indicate that this phytochemical [plant-derived compound] has tremendous potential in the treatment and prevention of cancer, particularly estrogen-enhanced cancer."

Clearly there is much more to I3C - and, most likely, its chemical cousins DIM and ascorbigen - than its effect (as important as that is) on estrogen metabolism via the 2/16-alpha-hydroxyestrone ratio. All the more reason to consider regular supplementation. With all these molecules eager to serve the cause of reducing your risk of estrogen-related cancer, it makes sense to try to optimize your molecular ratios and give your genes what they deserve: suppression of the harmful genes and enhancement of the good ones. That's "genetic engineering" we can all live with.

References

  1. Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr 2000;130:2927-31.
  2. Meng Q, Qi M, Chen DZ, Goldberg I, Rosen E, Auborn K, Fan S. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with upregulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med 2000;78:155-65.
  3. Fan S, Wang IA, Yuan RQ, Ma YX, Meng Q, Erdos MR, Brody LC, Goldberg ID, Rosen EM. BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses, and expression of cell regulatory proteins. Oncogene 1998;16:3069-82.
  4. Fan S, Wang JA, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KI, Goldberg ID, Rosen EM. BRCA1 regulates estrogen receptor signaling in transfected cells. Science 1999;284:1354-6.

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