Soybeans and Breast Cancer

Part II of a series on Phytoestrogens

January 1999; Volume 1: 12-14

By Adriane Fugh-Berman, MD

Soybeans and other phytoestrogens are being touted as breast cancer preventatives, but the real picture is not that clear. Although there is a rationale for a reduction in breast cancer risk in premenopausal women who consume a diet high in soy products, there is little evidence that soy benefits postmenopausal women and no evidence that it benefits women with breast cancer. And the phytoestrogen supplements proliferating on drugstore shelves may have very different effects than adding tofu to a stir-fry.

Soybeans, mainly in the form of fresh, dried, pressed, or fermented tofu, are a common food in China, Japan, Korea, and other Asian countries. Although several epidemiological studies show a protective effect of soy consumption on breast cancer risk, results are not entirely consistent.

Epidemiological Studies

A case-control study that compared food choices of 200 Chinese women with breast cancer in Singapore with 420 matched controls found that soy product intake had a protective effect in premenopausal women, but no effect on postmenopausal women.1 Another case-control study of premenopausal and postmenopausal women in China did not find a protective effect in either group.2

A recent case-control study of 288 premenopausal and postmenopausal women found that those with breast cancer excreted much lower amounts of phytoestrogens in their urine than women without breast cancer.3 In postmenopausal women, phytoestrogen supplementation markedly increased sex hormone binding globulin (SHBG);4 high levels of SHBG are associated with lower breast cancer risk.

A peculiar epidemiological study found a protective effect of miso (fermented soy paste) on breast cancer in a Japanese population living in Hawaii.5 The major problem with this study is that it used the dietary intake of husbands as a surrogate for their spouses. While couples eating together may have similar diets, in a number of these cases, the spouse was already dead and thus unavailable as a dinner companion. While it is possible that a widower’s diet reflects his dead wife’s diet, it may just as well reflect his mother’s or girlfriend’s, his own cooking, or the menu at the closest greasy spoon.

In Vitro and In Vivo Data

There are experimental data supporting the view that phytoestrogens may have a protective effect against breast cancer. Phytoestrogens are natural selective estrogen receptor modulators (SERMS) that have demonstrable hormonal effects on women. Genistein (an isoflavone that is the predominant phytoestrogen in soybeans) suppresses the growth of many cancer cells in vitro.6 In addition, genistein inhibits protein kinase, DNA topoisomerase, and several other enzymes involved in signal transduction. Results of studies in animal models of mammary carcinogenesis have been mixed.1

Reproductive Hormones

Phytoestrogen intake clearly has a strong effect on hormone levels in premenopausal women. Soybean intake substitutes weak estrogens for strong ones. Although phytoestrogens are less than 1% as potent as endogenous estrogens in binding assays, they can elicit equivalent biological responses.7 Because dietary phytoestrogens occupy estrogen receptors and fulfill the roles of endogenous estrogens, they down-regulate production of endogenous estrogens. Several studies have shown that serum estrogens are lower in Asian women than white Western women.8

This effect has also been demonstrated experimentally. A study of six premenopausal women found that daily consumption of 36 ounces of soy milk (containing about 200 mg isoflavones daily) for one month decreased serum 17-beta-estradiol levels by 81% at midcycle and 49% in the luteal phase.9 This decrease persisted for two to three cycles. Progesterone levels and DHEAS levels were also decreased. Menstrual cycle lengths increased by an average of 3.5 days, but because of the small sample size this difference was not statistically significant.

Another study of six women with regular menstrual cycles who consumed 60 g of soy protein (containing 45 mg isoflavones) daily for one month found that the heavy soy intake increased follicular phase length and/or delayed menstruation.10 Midcycle surges of luteinizing hormone and follicle-stimulating hormone were significantly suppressed as well.

Breast Secretory Activity

A study that examined the effects on nipple secretions in 24 premenopausal and postmenopausal women ingesting 38 g genistein-enriched soy protein isolate (containing 38 mg genistein) for five months found erratic elevations in estradiol concentrations, increased volume of breast secretions by nipple aspirate, and increased epithelial hyperplasia after supplementation.11 This was not a predicted finding. This study, however, is problematic and difficult to interpret, given a high dropout rate; possible stimulation of prolactin levels by breast pumping to obtain nipple aspirate; five women taking HRT or OC during the study; and the inexplicable inclusion of one subject despite the fact that she had a pituitary adenoma and was being treated with bromocriptine. Additionally, the product used was unusual, i.e., soy protein fortified with genistein.

Postmenopausal Women

Phytoestrogens may have different, and possibly opposite, effects in premenopausal and postmenopausal women. In premenopausal women, the effect of a diet high in phytoestrogens is anti-estrogenic, although in postmenopausal women phytoestrogens have estrogenic effects. The reason for this may be that because background estrogen levels are already low in postmenopausal women, adding dietary phytoestrogens increases estrogen effects, which is why phytoestrogen supplementation helps hot flashes. (See Premiere Issue of Alternative Therapies in Women’s Health).

Some argue that phytoestrogens must be beneficial at all ages because breast cancer rates are lower in Asian women throughout the life span at all ages than in Western women. However, lower postmenopausal breast cancer rates may have nothing to do with postmenopausal soybean intake. It may be that premenopausal soybean intake reduces lifetime risk of developing breast cancer. Additionally, other dietary and environmental differences may factor into this reduced risk. For example, Chinese and Japanese consuming a traditional diet consume more fiber, less fat, less meat, almost no dairy products, and more fruits, vegetables, and grains than do Westerners. Any of these factors (or a combination) could contribute to lower breast cancer rates.

Women with Breast Cancer

There are no clinical studies of the effect of phytoestrogen intake in women with breast cancer. It may be theorized that in premenopausal women with breast cancer, the reduction in endogenous estrogens by soy food supplementation would be beneficial. In postmenopausal women with breast cancer, there is little reason to think that soy food supplementation would be beneficial. It is unclear what the combined effects of tamoxifen treatment and soy supplementation would be.

Phytoestrogens can cause cancer cells to grow. In an immunocompromised mouse model, phytoestrogen implants caused estrogen receptor positive (but not estrogen receptor negative) breast cancer implants to grow.12 A recent in vitro study found that four types of phytoestrogens (genistein, daidzein, formononetin, and equol) stimulated estrogen-dependent gene expression in MCF-7 breast cancer cells.13 Combinations were even more stimulatory than individual compounds.

Soy and Endometrial Cancer

Unlike conjugated estrogens or the SERM tamoxifen, soy foods do not increase endometrial cancer rates and in fact may decrease it. A case-control study of 332 endometrial cancer cases and 511 controls among a multi-ethnic population in Hawaii found that high soy intake appears to protect against endometrial cancer in both premenopausal and postmenopausal women.14

Recommendations

In premenopausal women, soy food supplementation lowers endogenous estrogen levels and may help reduce the rate of breast cancer occurrence or recurrence. There is no convincing evidence that soy food supplementation prevents breast cancer occurrence or recurrence in postmenopausal women, nor is there convincing evidence that soy supplementation is harmful. There is a dearth of information on combining soy food supplementation with tamoxifen.

Soy foods have been a staple in Asian cuisine for thousands of years and can be presumed safe. However, the recent availability of purified isoflavone or mixed-phytoestrogen pills is worrisome. There are no long-term safety data available for these food-free phytoestrogens, and their use should be discouraged.

References

1. Lee HP, et al. Dietary effects on breast-cancer risk in Singapore. Lancet 1991;337:1197-1200.

2. Yuan JM, et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995;71:1353-1358.

3. Ingram D, et al. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997;350;990-994.

4. Brzezinski A, et al. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4:89-94.

5. Nomura A, et al. Breast cancer and diet among the Japanese in Hawaii. Am J Clin Nutr 1978;31: 2020-2025.

6. Messina MJ, et al. Soy intake and cancer risk: A review of the in vitro and in vivo data. Nutr Cancer 1994;21:113-131.

7. Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol 1996;87:897-904.

8. Rose DP. Dietary fiber, phytoestrogens, and breast cancer. Nutrition 1992;8:47-51.

9. Lu LJ, et al. Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer risk reduction. Cancer Epidemiol Biomarkers Prev 1996;5:63-70.

10. Cassidy A, et al. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-340.

11. Petrakis NL, et al. Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev 1996;5:785-794.

12. Helferich WG. Paradoxical effects of the soy phyto-estrogen, genistein on growth of human breast cancer cells in vitro and in vivo. Presented at Human Diet and Endocrine Modulation: Estrogenic and Androgenic Effects. International Life Sciences Institute of North America; November 19-21, 1997; Fairfax VA.

13. Willard ST, Frawley LS. Phytoestrogens have agonistic and combinatorial effects on estrogen-responsive gene expression in MCF-7 human breast cancer cells. Endocrine 1998;8:117-121.

14. Goodman MT, et al. Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol 1997;146:294-306.