Should breast cancer patients eat or avoid phytoestrogens?

For awhile now, women have received conflicting data about how the consumption of soy products affects breast cancer. While soy is often touted as a cancer-prevention food, diagnosed Western patients in particular have generally been scared off of soy, because the plant contains phytoestrogens, which can mimic the action of estrogens.

The uncertainty surrounding the risks and benefits of phytoestrogens involves that of non-human chemicals in general that are capable of binding with human hormone receptors. When a compound other than estrogen binds with an estrogen receptor, it can have one of two effects: it can have a similar effect as estrogen itself, stimulating estrogenic effects, or it can have the opposite affect, serving as a block for estrogen, thereby reducing estrogenic effects.

It gets even more complicated than this, because there are estrogen receptors all over the human body, even in men, and there are at least two types of receptors, alpha (?) and beta (?). Furthermore, estrogenic effects of phytoestrogens are several orders of magnitude below those of true estrogen. (It is for this reason that even before the studies discussed below were published, many oncologists including Dr. Susan Love have said that women with breast cancer should not worry about eating soy foods in moderation.)

Here’s a little more about what is known about phytoestrogens. They can be divided into three main classes: isoflavones (over a thousand chemicals found in soy-based foods), lignans (fruits, vegetables, and grains), and coumestans (found in alfalfa sprouts). Of these, isoflavones appear to be the most potent. Another weak phytoestrogen is resveratrol (the compound in wine made from red grapes that is associated with anti-aging and anti-cancer effects).

Below is a chart of phytoestrogen amounts in different soy foods, taken from a phytoestrogen report by the Hospital for Special Surgery in New York. (A relatively high intake of isoflavones would be on the order of an average of 60 mg per day):

Food Phytoestrogen Content
Miso 30 mg per 1/4 cup
Soybeans 40 mg per 1/2 cup
Soyflour 25 mg per 1/4 cup
Tempeh 40 mg per 1/2 cup
Tofu 40 mg per 1/2 cup
Soy Milk 40 mg per 1 cup
Roasted Soybeans 162 mg per 3 1/2 ounces
Textured Vegetable Protein 138 mg per 3 1/2 ounces
Green Soybeans 135 mg per 3 1/2 ounces
Tofu yogurt 16 mg per 3 1/2 ounces
Soy hot dog 15 mg per 3 1/2 ounces
Soy noodles (dry) 8.5 mg per 3 1/2 ounces

But although epidemiological studies for years have indicated that diet has a role in the likelihood of developing breast cancer, it has remained unclear whether phyotestrogens are specifically protective, or whether they are just associated with a healthy diet in general.
This is because the interaction of the many different phytoestrogens with hormones and receptors in our bodies turns out to be highly complex.

In general, the amount of estrogen in the blood seems to be reduced by the intake of phytoestrogens. There is some mixed evidence that increasing phytoestrogens may lengthen the menstrual cycle as well. This would provide indirect protection against breast cancer, as it would reduce exposure of cancer cells to estrogen over a lifetime.

The mechanism by which phytoestrogens reduce estrogen in the body seems to be that they interfere with the enzymes involved in estrogen production, particularly cytochrome P450 19 aromatase. (It is known that people with higher levels of these enzymes are more likely to have breast cancer.) They therefore function as aromatase inhibitors, similarly to the commercial drugs Femara, Arimidex, and Aromasin, which are now commonly prescribed to post-menopausal women with breast cancer.

But it is more complicated than this, of course; just as estrogens have different effects depending on how they interact with estrogen receptors in different parts of the body, some phytoestrogens can increase aromatase activity in some areas.

One potentially important difference between phytoestrogens and estrogen is that while estrogen binds equally to ER-α and ER-β receptors, phytoestrogens have a higher affinity for ER-β. A higher number of ER-α receptors is associated with more aggressive malignant tumors. ER-β receptors seem to have antiproliferative (= anticancer) effects that are induced when they are bound.

Even though phytoestrogens have a lower affinity for estrogen receptors in general, some seem to induce a greater response from those receptors than estrogen itself. The presence of estrogen seems to influence this effect. And so, phytoestrogens can promote cell growth in ER-positive cancer cells. In the case of ER-negative cells, the effect appears to be the opposite.

On top of this, phytoestrogens seem to alter estrogen-metabolizing enzymes, which affects how quickly estrogen is broken down in your system, and also the levels of estrogen metabolites, some of which are known to be carcinogenic.

All this together shows that there is still no simple answer on inhibitory vs. proliferative effects on cancer cells in general for phytoestrogens, because there is variation among the different phytoestrogens, and studies have had conflicting results even for the same compound. It is important to remember that these compounds do not function in a vacuum, and the overlying hormonal environment, which is ever changing in women, will have an influence. This means that whether phytoestrogens inhibit or stimulate cancer cells depends at a minimum on 1) the specific phytoestrogen compound, 2) its concentration in the blood, 3) whether cancer is yet present, and if so, the stage and other pathology of the tumor and 4) the general hormonal environment in the person at the time of exposure – both age and menopausal status clearly matter. Effectively this means that there is no rule for whether or not it is good or bad to consume phytoestrogens, and there probably will never be, even if we determine the effects of the compounds in a given context at a detailed level.

For example, one study found that in mice whose ovaries had been removed (and therefore rendered “post-menopausal”), the phytoestrogen genestein stimulated tumor growth, rather than inhibiting it. A possible explanation was that phytoestrogens exhibit estrogenic activity in a low estrogen environment, but anti-estrogenic activity when there is more estrogen in the blood. Other studies have shown that genestein inhibits the growth of breast cancer cells. The timing of phytoestrogen intake is thus important. Mice fed genestein when they were young had fewer breast tumors later compared with those fed it later in life.

Even when anticancer effects have been found, most studies have been done in vitro (in a petri dish, not in a human) and often much larger doses of the phytoestrogens than could be obtained by diet alone were required to demonstrate tumor-inhibiting effects.

There is also an interesting idea that phytoestrogen intake over one’s life could actually influence the ER status of breast cancer when it occurs. This is because lower estrogen levels in the blood, which can be an effect of phytoestrogens, stimulate ER expression. In a study of 124 premenopausal breast cancer patients, 18 individual and 5 classes of phytoestrogens were examined for this relationship, to find out which, if any, were more strongly associated with the development of ER-negative disease than ER-positive disease in premenopausal women with breast cancer. They looked only at the status of ER-α receptors.

The study found evidence that the isoflavones genistein and daidzein (both found in soy and other legumes) could enhance ER expression in breast cancer cells, through the above mechanism.

One recently publicized study was done on Chinese women with breast cancer, to find out how soy consumption might affect cancer recurrence. It was based on questionnaires, with a 3 year follow-up. On the surface, there was a striking result that among the highest soy consumers, taking tamoxifen did not incur an added benefit.

However, the positive effects encompassed nearly every possible group: pre- and post-menopause, ER-positive and ER-negative, and both early- and late-stage cancers. The broad consistency of this result suggests that this type of study is a blunt instrument that may still not be too useful in informing individual dietary decisions. The study had the inherent weakness of being retrospective instead of controlled, and related to that, the sample size of >5000 is large, which increases its power to detect small differences. In comparing (roughly estimated) phytoestrogens ingested between the group with the highest soy intake and the group with the lowest soy intake, the hazard ratios (likelihood of death or recurrence for highest intake group vs. lowest intake group) were at best barely significant, which suggests a low biological significance of this result, because small effects are more likely to be significant statistically when you are working with a large sample size.

In another study by the same research group of 73,223 Chinese women, adult soy food consumption, measured either by soy protein or isoflavone intake, was inversely associated with the risk of premenopausal breast cancer. No significant association with soy food consumption was found for postmenopausal breast cancer. This study was so huge that it included thousands of cancer patients. So again, one must be wary of the extreme statistical power being used in these studies, and whether such power implies more biological significance than there actually is.

In conclusion, although there is evidence that a diet rich in phytoestrogens can promote breast cell proliferation in the short-term, all the available evidence taken together still suggests that consuming a lot of phytoestrogens does not increase the risk of breast cancer, and may indeed protect against it. It is still impossible to reconcile dietary/supplement exposure with epidemiological and experimental studies, and some researchers worry that women may take high doses of ‘natural’ phytoestrogens and end up with levels high enough in their blood that might have a negative impact on their long term health.

As with all foods, moderation is the key. There is almost never any real reason for a well fed Westerner to take any supplements, and that is really the only way that one could overdose on phytoestrogens. Whether or not you have had breast cancer, a moderate amount of soy in your diet is not likely to affect your outcome dramatically. So Shelley Lewis, who as related in her breast cancer memoir made the unhappy decision to cut off all soy in her diet, should take heart that there is not likely to be any harm in enjoying edamame now and then – and it may even be beneficial.

References

Glazier MG, Bowman MA, 2001. A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Archives of Internal Medicine 161(9):1161-72.

Lee SA, Shu XO, Li H, Yang G, Cai H, Wen W, Ji BT, Gao J, Gao YT, Zheng W, 2009.
Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women’s Health Study. American Journal of Clinical Nutrition 89(6):1920-6.

Mense SM, Hei TK, Ganju RK, Bhat HK., 2008. Phytoestrogens and breast cancer prevention: possible mechanisms of action. Environ Health Perspect. 116(4):426-33.

Rice S, Whitehead SA. , 2006. Phytoestrogens and breast cancer–promoters or protectors? Endocr Relat Cancer13(4):995-1015.

Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W, 2009. Soy food intake and breast cancer survival. JAMA. 302(22):2437-43.

Touillaud MS, Pillow PC, Jakovljevic J, Bondy ML, Singletary SE, Li D, Chang S. , 2005. Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutrition and Cancer 51(2):162-9.

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2 Responses to “Should breast cancer patients eat or avoid phytoestrogens?”

  1. Gina says:

    Of course, young women, who have the highest estrogen levels, have the lowest overall rate of breast cancer, and this seeming paradox is generally ignored when formulating advice and guidelines for older women. This says to me that the endocrine system is very poorly understood, no matter what the medical societies pretend.

    Full disclosure: I am hypothyroid as a consequence of Hashimotos’s disease, and I can say from painful experience that the medical profession is almost willfully ignorant about hypothyroidism. It’s obvious to me that the even more complex interactions of sex hormones would necessarily baffle the docs (though they will never admit it).

  2. Biotunes says:

    It’s not a paradox, because you are ignoring a very important part of the equation – higher breast cancer rates are associated with higher number of menstrual cycles, because each time cells proliferate during a cycle, there is the possibility that a mutated (=cancer) cell will be proliferated, setting in motion the possibility of invasive cancer. Age is simply a huge factor that is at least as important as current estrogen levels – and of course age is probably the biggest predictor for nearly (but not all) cancers because the longer our bodies are around, the more times cells reproduce through mitosis, and the bigger the chance that a mistake will be made during cell reproduction that will lead to cancer.

    Of course there is a lot more to be discovered about the endocrine system and cancer, but one aspect of cancer that’s pretty straightforward is why older people are more likely to get it.

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