More than two-thirds of breast cancers make the estrogen receptor. What that means is that these tumors have the protein receptor that binds estrogen, which then activates the receptor and causes all the genes that are turned on or off by estrogen to be turned on and off. That's how estrogen acts on normal breast epithelial cells and on breast cancer cells. The significance of this observation is that estrogen receptor-positive (ER+) breast cancers respond to estrogen. Indeed, estrogen contributes to their growth, and blocking estrogen is an effective treatment against them. Indeed, that most breast cancers are estrogen-responsive has been understood for decades. Long ago, a standard treatment for breast cancer in reproductive age women was oophorectomy, the removal of the ovaries, in order to produce an early menopause.
Surgical approaches to decreasing the level of estrogen in a woman's body were supplanted by the use of tamoxifen, an estrogen analogue that started its life as a candidate to be a birth control pill but didn't work out for that. The simplistic view of tamoxifen is that it is an estrogen receptor blocker, and indeed it does bind to the estrogen receptor and keep estrogen from binding to it. However, we now refer to tamoxifen as a selective estrogen response modulator (SERM) because it turns out that tamoxifen blocks the action of estrogen in some tissues (for example, breast, where its estrogenic activity is much weaker than that of estrogens and why it mostly blocks estrogen activity--hence its use to treat breast cancer) and mimics it in others (for example, bone). Until recently, tamoxifen has been the mainstay of treatment for ER+ breast cancers, as it is effective (it provides at least as much benefit as chemotherapy when used in the adjuvant setting) and relatively safe. True, it has side effects, but those are related to its blockade of estrogen activity, which in essence induces a menopause-like state, complete with hot flashes that can be difficult to treat (so much that women and their physicians can be tempted by woo to treat it).
More recently, another class of drugs, the aromatase inhibitors, has become a mainstay of the treatment of breast cancer as well. Their mechanism of action is to inhibit an enzyme called aromatase, which converts androgens to estrogens in the peripheral tissues by a reaction that looks like this in the case of testosterone being converted to estradiol:
(Yes, I stole this from Wikipedia's entry on aromatase inhibitors, but what the heck? An illustration is an illustration, and I know this one is in the public domain. This reaction happens outside of the ovaries in the peripheral tissues. In the postmenopausal woman, this reaction is the main source of the low levels of estrogen that remain in the bloodstream. The adrenal glands make androgens, and aromatase converts these androgens into estrogens in the peripheral tissues, mainly the adipose and skin fibroblasts, although breast cancer cells not infrequently make aromatase too. Indeed, in a premenopausal woman, aromatase is not a significant source of estrogen, as the ovaries continue to crank out massive (comparatively speaking, anyway) quantities of estrogens. That's why aromatase inhibitors are generally not useful in the treatment of breast cancer in premenopausal women. There's just too much estrogen being made by the ovaries.
If there is one principle of treating ER+ breast cancer, however, it is that it is desirable to block the action of estrogen on the breast cancer as much as possible. Tamoxifen does this primarily by competing with endogenous estrogen for binding to the estrogen receptor, and aromatase inhibitors accomplish this by lowering the tissue levels of estrogen by preventing it from being made. Both strategies are highly effective, but in postmenopausal women it is generally agreed that aromatase inhibitors are probably somewhat more effective in general than tamoxifen, which is why they have mostly supplanted tamoxifen as the standard of care for breast cancer in postmenopausal women. Exceptions exist, of course. For example, care is required in women who may be prone to osteoporosis because aromatase inhibitors can increase the risk of bone loss and fracture.
One thing that is generally considered a bad idea is to raise the estrogen level in women with breast cancer or to raise the level of compounds with estrogen-like activity. That's one reason why I've been so harsh in denouncing Suzanne Somers, who, even though a breast cancer survivor herself, advocates the intake of massive quantities of so-called "bioidentical" hormones as a veritable fountain of youth. Of course, she previously eschewed adjuvant chemotherapy after the surgical resection of her tumor. (I don't recall if she eschewed radiation as well.) Naturally, now she attributes her survival to the "alternative" medicine treatments she underwent rather than to surgery, as is common, but I remain disturbed that she would continue to espouse the use of "bioidentical" estrogens, even in women with breast cancer. It defeats the purpose of the treatment to introduce estrogens, whether "synthetic" or "bioidentical" back into the system and increases the risk of recurrence. Indeed, witness how hormone replacement therapy has so rapidly fallen out of favor because it was linked to an increased risk of breast cancer.
All of this is my roundabout way to provide the background for a new study that I just saw that suggests that a certain commonly used supplement may do the same sort of thing as bioidentical hormones. This study, by William Helferich a Professor of Food Science and Human Nutrition at the University of Illinois, was recently published electronically ahead of print and is entitled Dietary Genistein Negates the Inhibitory Effect of Letrozole On The Growth Of Aromatase-expressing Estrogen-Dependent Human Breast Cancer Cells (MCF-7Ca) In Vivo. First, the press release:
CHAMPAIGN, Ill. -- Women taking aromatase inhibitors to treat breast cancer or prevent its recurrence should think twice before also taking a soy-based dietary supplement, researchers report.
Genistein, a soy isoflavone that mimics the effects of estrogen in the body, can negate the effectiveness of aromatase inhibitors, which are designed to reduce the levels of estrogens that can promote tumor growth in some types of breast cancer.
The new study, which included researchers from the University of Illinois, Virginia Polytechnic and State University and the National Center for Toxicological Research, appears in the journal Carcinogenesis.
Aromatase inhibitors are a mainstay of breast cancer treatment in post-menopausal women. These drugs work by interfering with the enzyme aromatase, which catalyzes a crucial step in converting precursor molecules to estradiol, the main estrogen in the body.
About two-thirds of all cases of breast cancer diagnosed in the U.S. are estrogen dependent or estrogen sensitive, which means that the tumors grow more rapidly in the presence of estrogen.
Most women diagnosed with breast cancer are post-menopausal, so their ovaries are no longer producing normal levels of estrogen. Other tissues, however, produce a steroid hormone, androstenedione (AD), which - with the help of aromatases - is converted to testosterone and estrogens. The estrogens produced from AD can stimulate the growth of some types of breast cancer tumors.
The researchers conducted several trials in a mouse model of estrogen-dependent post-menopausal breast cancer. First, they gave the mice AD, which was converted to estrogen and created a high estrogen environment.
This helped the researchers determine the maximum growth rate of the breast cancer tumors.
Next, they added Letrozole, an aromatase inhibitor widely prescribed to post-menopausal women with estrogen-dependent breast cancer. This treatment (Letrozole) effectively blocked the effects of AD and the breast cancer tumors stopped growing.
But when they added genistein (a plant estrogen or "phytoestrogen" present in many dietary supplements) to the mix, the researchers observed a dose-dependent reduction in the effectiveness of the breast cancer drug. Specifically, the tumors began to grow again. They grew fastest at the highest dietary doses of genistein.
"To think that a dietary supplement could actually reverse the effects of a very effective drug is contrary to much of the perceived benefits of soy isoflavones, and unsettling," said William Helferich a professor of food science and human nutrition at Illinois and principal investigator on the study. "You have women who are taking these supplements to ameliorate post-menopausal symptoms and assuming that they are as safe as consuming a calcium pill or a B vitamin."
Many women take genistein supplements to control hot flashes and other symptoms of menopause. The researchers found that the doses commonly available in dietary supplements were potent enough to negate the effectiveness of aromatase inhibitors.
Actually, this is a pretty darned good lay person-accessible description of how the study was done. Back in 2002, these same investigators did a series of experiments that showed essentially the same thing with tamoxifen: That genistein can negate the inhibitory effect of tamoxifen on breast cancer cells. The current study produced a result that looked like this:
Note: AD = androgen (to assure that there is androgen for aromatase to convert into estrogen); LET = letrozole, an aromatase inhibitor; and GEN = genistein.
As the amount of genistein fed to the mice increases, you note that the growth rate of the tumor increases from basically being totally suppressed by letrazole (Femara) to growing briskly, albeit not as fast as in the AD alone group. In any case, the implication is clear: Increasing intake of genistein is associated with increased tumor growth and resistance to letrazole.
So does this mean that genistein or other soy phytoestrogens, which have been billed as "safe" estrogenic compounds, stimulate breast cancer growth? Well, it's not so clear. Certainly these animal models suggest it. However, one must remember that this is a highly artificial model in that the mice have been oophorectomized and therefore don't make enough estrogen to support the growth of MCF-7 cells. (MCF-7 is one of the most commonly used ER+ breast cancer cell lines; it was derived from the pleural effusion of a woman with stage IV breast cancer in 1970.) Estrogen must be provided, either in the form of estrogen itself or in the form of androgens that can be converted to estrogen, for MCF-7 cells to grow in immune deficient mice as xenografts. How much this model relates to humans is unclear, but it does provide a plausible mechanism by which genistein might interfere with antiestrogen therapy.
In fact, there has been some interest in whether genistein or other soy phytoestrogens might in fact be preventative for breast cancer, based on the the observation of a lower incidence of breast cancer in countries where soy consumption is higher than in the U.S. There is also evidence that genistein can itself actually function as an aromatase inhibitor at high enough doses. Moreover, the idea that soy is a useful treatment for menopausal symptoms has taken hold, despite the paucity of evidence that it works. As Professor Helferich notes in the article:
Isoflavone-containing dietary supplements are among the most widely consumed by older women, however, the effects of isoflavone supplements on postmenopausal symptoms in human trials are at best inconsistent in producing beneficial effects [41,42]. The interaction of estrogenic isoflavone supplements with prescription drugs for breast cancer is a critical health issue that has not been adequately investigated.
Other investigators point out that there is no real evidence in humans that the consumption of genistein or other soy products increases the risk of breast cancer. Indeed, a recent meta-analysis concluded:
Soy intake may be associated with a small reduction in breast cancer risk. However, this result should be interpreted with caution due to potential exposure misclassification, confounding, and lack of a dose response. Given these caveats and results of some experimental studies that suggest adverse effects from soy constituents, recommendations for high-dose isoflavone supplementation to prevent breast cancer or prevent its recurrence are premature.
A recent workshop examining the issue made these recommendations:
Neither the existing animal nor human data allow definitive conclusions to be drawn about the effect of soyfoods or isoflavones on breast cancer risk in high-risk women and on the survival of breast cancer patients. There is an important public health imperative to determine the safety of soyfoods in both groups of women. Definitively establishing that soyfoods do not adversely affect the survival of breast cancer patients may not be possible. To do so will likely require conducting a long-term intervention trial in which tumor recurrence or survival are endpoints. However, conducting such studies may be prohibitively expensive and raise ethical concerns. Assessing the potential impact of soyfoods on breast cancer risk in high-risk women is possible by examining cancer risk markers (e.g., cell proliferation, apoptosis) using breast tissue samples obtained via RPFNA or ultrasound-guided biopsies. Such research is urgently needed and should be designed to determine both safety and efficacy. Careful consideration should be given to the types of soy products used for such interventions; emphasis should be placed on using products that allow findings to be extrapolated to as broad a range of soy products as possible.
So what's the bottom line? Certainly the mouse studies suggest a plausible mechanism by which genistein might interfere with antiestrogen therapies. On the other hand, there is pretty close to zero human evidence that soy isoflavones have any effect, positive or negative, on a woman's risk of breast cancer. There are also some studies from Asia that tried to correlate rates of survival and recurrence with the intake of soy and found no differences, although the studies are not definitive. Since the only true definitive study, a randomized prospective study in which women would be randomized to either aromatase inhibitor or aromatase inhibitor plus genistein can't be done because of ethical considerations, epidemiological studies and prospective observational studies are the best evidence we will be able to come up with. In addition, there is evidence that timing matters. Soy exposure during adolescence may be protective against breast cancer while later in life the relationship is not so clear. There's also a fascinating potential issue of the level of processing of the soy. The same group has reported that more highly processed soy products are more estrogenic and therefore more stimulatory towards breast cancer in animal models than less processed versions, even when the amount of genistein is the same. If true, this would suggest that it could potentially be far worse to consume soy supplements than it would be to consume the same amount of soy just in food. I bet the supplement manufacturers won't tell you that.
One ongoing study that might shed some light on this question is a study that was described thusly in the above workshop report:
The impact of soy intake on recurrence or survival of breast cancer patients can be evaluated in an epidemiologic setting. In this regard, Anna Wu (University of Southern California, Los Angeles, CA) presented the experimental design for her ongoing investigation of the effects of lifestyle factors on breast cancer prognosis among Asian-Americans. A total of 1378 case patients are in the study, including 489 Chinese, 383 Japanese, and 506 Filipino women, all of whom reside in the Los Angeles area. Data are being collected about initial treatment and tumor characteristics--tumor stage and size, lymph node status, extent of disease, histology, differentiation, grade, laterality, and estrogen-progesterone receptor status--as provided by the Los Angeles County Cancer Surveillance Program (member of the Surveillance End Results Program). Telephone interviews are being conducted 5 years after initial diagnosis of breast cancer to determine lifestyle characteristics, including body weight, physical activity, herbal and vitamin supplement use, and dietary pattern (main food groups include soy, tea, fruits and vegetables, red meat, white meat, fish, and alcohol). Postdiagnostic follow-up data also being collected include the number and type of breast surgeries and use of tamoxifen, raloxifene, aromatase inhibitors, herceptin, chemotherapy, radiation, and other conventional treatments, as well as the use of alternative or complementary therapy. Data collection will be completed in 2008.
We're not likely to see the results of this study for while, as it will take time to analyze the data even if data collection was completed this year as planned. So what to do in the meantime? After all, this is where the rubber hits the road when it comes to science- and evidence-based medicine: How does a clinician make recommendations based on inadequate evidence and suggestive animal studies? My approach is cautious. Given the animal studies and relative lack of strongly correlative studies, my tendency would be to recommend to my breast cancer patients avoiding soy supplements and large amounts of soy while actively under treatment (i.e., while taking tamoxifen or an aromatase inhibitor, the course of treatment for which is usually five years) and that it may not be a great idea to use it afterward but that we just don't really know. As for other women, I don't see any reason to counsel them to avoid soy or genistein at the moment. I may change that recommendation based on new data, but for now that's my story and I'm sticking to it.
I'm also not all that enthusiastic about it.
REFERENCE:
Y. H. Ju, D. R. Doerge, K. A. Woodling, J. A. Hartman, J. Kwak, W. G. Helferich (2008). Dietary Genistein Negates the Inhibitory Effect of Letrozole On The Growth Of Aromatase-expressing Estrogen-Dependent Human Breast Cancer Cells (MCF-7Ca) In Vivo Carcinogenesis DOI: 10.1093/carcin/bgn161
Nice post Orac!
The situation reminds me somewhat of the debate on whether HRT increases or reduces the incidence of heart disease. With HRT the time interval between the start of menopause and start of HRT seems to be a factor, with shorter times being associated with a decrease in risk and longer times with an increase in risk. Unfortunately there is also a lack of data and confusion due to the use of different regimes.
hmmmm this should be interesting to the 'anti soy' subculture (typically religious fundies in the US) who feel that estrogen action from soy is causing an epidemic of homosexuality and health problems.
Thanks for the interesting read, Orac.
Bill Helferich and his students and colleagues have really done a terrific job in this area over the last several years; I know some folks who were actually investigating this aspect of soy with SERMs and aromatase inhibitors so Bill's group was indeed addressing an important question.
I'd be interested in two other related issues: 1) what do soy supplements do in the context of this animal model?; most if not all soy supplements sold to people are comprised of genistein plus other isoflavones, many of which are present in higher quantities than genistein (it is expensive to separate genistein from the related compounds so dietary supplement companies don't normally do it). 2) Does phenoxodiol also antagonize aromatase inhibitors in this model?: phenoxodiol is a semi-synthetic derivative of genistein that is being developed as a conventional, single-agent chemotherapeutic by the Australian company, Marshall-Edwards. It apparently has weak ER binding activity and is in clinical trials, mostly for taxane-resistant ovarian cancer, but may ultimately expand to breast cancer since taxanes are used in that setting as well.
Anyway, a very nice post on some very nice work.
Motivation is a fire from within. If someone else tries to light that fire under you, chances are it will burn very briefly.
Funny that you should post on this subject, as I am presently attending a conference on steroidal hormones and cancer (http://www.ichshc2008.com/ ; tomorrow is the last day).
There was an interesting talk yesterday which might point out why this subject (HRT using phytoestrogens and other serms) is more complicated than it would seem. There are actually two subtypes of ER : ERalpha and ERbeta. They are pretty similar in their DNA binding domains but quite different in their ligand binding domains. That means certain molecules will bind one more than the other, but that they essentially bind the same promoters, which we call the EREs (for Estrogen Response Element). The surprising thing is that they have pretty different effects if you look at gene transcription: ERalpha increases transcription levels for proliferative genes, and ERbeta increases trancription for tumor suppressor genes.
It is possible to obtain high levels of selectivity for ERbeta vs ERalpha. Pharma companies have begun programs for selective ERbeta agonists since its discovery in the late 90s. They have potential as cancer treatment as well as many other applications.
Some phytoestrogens are known to have preference in binding ERbeta. This might severely complicate any epidemiological study, especially if done over a general "phytoestrogen" theme (or even, for example, if you use "isoflavones" as a subject since molecules of the same structural class can also have huge selectivity differences), when it becomes more and more apparent that those different molecules have very different effects, due to their activities as inhibitors of steroidogenesis but also to their subtype preference.
Bottom line of this : don't take a pill when you have no idea what it contains. "Phytoestrogens" (or as they are hilariously called, since they are not even freaking steroids, "bioidentical hormones") is a class of chemicals (which does not depend on structure but on ER agonist activity) which contains many types of molecules with a wide range of affinities for the two ER subtypes and/or other poorly defined activities. No effective drug, whether you extract it from natural source or synthesize it, is devoid of side effects.
Would the use of a noncompetitive estrogen-receptor antagonist (since Tamoxifen sounds like it's competitive) mitigate the risk both excess endogenous estrogen production and exogenous estrogen ligands? Or would this be one of those Very Bad Ideas due to potential side effects?
I need to bookmark this discussion as an example of how real science-based medicine approaches a subject that is undecided versus how a woo-based disciple approaches the chance for a sale.
Prostate cancer in men behaves very similar to breast cancer. Unfortunately soy based compounds are promoted for this as well, which can have just as negative an effect.
A receptor antagonist is pretty much competitive by definition, as opposed to an enzyme inhibitor. One of the ways the potency of an antagonist is measured is by doing the RBA (Receptor Binding Assay), which is a direct measure of how much the tested compound competes for the receptor with the endogenous ligand (estradiol). An ER binder can be either an agonist or an antagonist. That depends on whether or not they promote gene transcription. It is now known that ER antagonists stop transcription by hindering some conformational changes in the ligand-binding domain of ER (if you are interested, look up helix 12 folding) and therefore precludes the binding of proteins which allow the recruitment of transcription machinery.
Theoretically, you could have compounds which would stop transcription by binding to oher domains of the ER and/or hinder protein-protein interactions, but I wouldn't call those antagonists. However you would face an important, but probably not impossible to overcome, problem of selectivity, since you will be dealing with proteins that are common to many transcription factors.
The second strategy, which is already exploited in the clinic (see arimidex) is that of steroidogenesis inhibitors. It works particularly well in post-menopausal ER+ breast cancer (that is, the majority of cases). Some women find that it works too well : the menopause symptoms are so severe that they are forced to discontinue treatment, or worse seek a hormonal replacement from their GP, which often doesn't understand that he is essentially nullifying the oncologist's treatment (one colleague of mine had to go shouting at his mother's GP for doing just that).
There is even a complementary strategy that is being explored for prostate cancer, that is to flood the system with receptor binding domains to capture existing hormone. This strategy is clever since it avoids one bad consequence of antagonists, that is positive feedback (upregulation of hormone biosynthesis) by the gonado-hypophyso-hypothalamic axis (secretion of LHRH). The drawbacks being, of course, the difficulty of administering peptide drugs, and their staggering preparation cost.
But all of these approaches have their limit : after a while (about 2 years for the andogen receptor, about 5 years for ER), receptors become permanently activated, and thus ligand independant, by phosphorylation.
That's why I think that ERbeta agonists will soon have their say in the hormonal treatment of breast cancer. As more becomes known on ERbeta's role in modulating ERalpha transcription activity independently of ligand binding, it is becoming a more attractive therapeutic target.