October 04, 1999
American Journal of Clinical Nutrition, Vol. 70, No. 4, 574-57
American Society for Clinical Nutrition
Letters to the Editor
Soy, soy phytoestrogens (isoflavones), and breast cancer
Nutrition Matters, Inc, 1543 Lincoln Street, Port Townsend, WA 98368, E-mail: email@example.com
McMichael–Phillips et al (1) found that daily consumption (60 g) of a soy–protein product containing 45 mg isoflavones for 2 wk stimulated DNA synthesis in breast cells taken from biopsies of premenopausal women with benign and malignant breast disease. These findings suggest that soy may actually exert estrogenic rather than antiestrogenic effects on breast tissue. This is not the first human study to suggest such an effect. Petrakis et al (2) found that in premenopausal women, daily soy consumption for 4 mo was associated with an increase in breast nipple fluid aspirate secretion and breast cell hyperplasia. However, this study did not include a control group and fluid secretion increased in women even after soy feeding was discontinued. Nevertheless, both studies raise important questions about the effect of soy isoflavones on breast tissue.
The study by McMichael–Phillips et al is particularly noteworthy, assuming that the increased DNA synthesis reflects an increase in cell proliferation. Increased cell proliferation has traditionally been considered a marker for increased cancer risk. However, this notion was challenged recently, at least with regard to the colon (3). In addition, as discussed below, there is reason to question whether the increased breast cell proliferation in response to soy consumption should be interpreted in a unfavorable light.
In the assessment of cancer risk, cell proliferation is only one side of the equation, the other being apoptosis. Illustrative of the need to look at both sides of the equation is the finding that the nonsteroidal antiinflammatory drug sulindac enhances cell proliferation in 1,2–dimethylhydrazine–treated mouse colonic mucosa, but inhibits 1,2–dimethylhydrazine–induced colon tumors (4). Moorghen et al (4) suggest that sulindac inhibits carcinogenesis despite the increase in cell proliferation because proliferation in this case is a compensatory response to an even larger increase in apoptosis. Because genistein, the primary isoflavone in soybeans, causes apoptosis in breast cancer cells in vitro, perhaps a similar phenomenon occurs with soy in vivo as it does with sulindac. Consistent with this suggestion is recent research showing that soy isoflavones markedly inhibited transplantable murine bladder cancer; however, although cell proliferation decreased slightly, apoptosis increased as much as 2–3– fold (5).
As pointed out by McMichael–Phillips et al, the short–term nature of their study is an important consideration, especially because of a report showing that tamoxifen increased pS2 expression(suggesting an estrogenic effect) in the breast tissue of breast cancer patients after 6 wk of administration but that this effect was reversed after 6 mo of treatment (6). Related to this finding is the finding that chronic exposure to isoflavones in vitro down–regulates the estrogen receptor. If down–regulation takes > 2 wk to occur in people eating soyfoods, any effect on cell proliferation would not have been detected by McMichael–Phillips et al. Similarly, the increase in follicular phase length in response to soy consumption that has been observed by some investigators would not be apparent after only 2 wk of soy feeding. Increasing follicular phase length could decrease breast cancer risk in the long term.
Although 2 recent studies failed to show an effect of soy on cycle length, soy was found recently to favorably affect estrogen metabolism in premenopausal women—increasing the urinary ratio of 2– to 16a–hydroxylated estrogens and of 2– to 4–hydrox–ylated estrogens (7). Again, this change in estrogen metabolism would likely not occur rapidly enough to affect cell proliferation after only 2 wk of soy feeding.
Overall, there are inconsistent data regarding the likely estrogenic and antiestrogenic effects of soy on breast tissue. In vitro studies suggest that the isoflavones are estrogenic, not antiestrogenic. Although partial and pure antiestrogens demonstrate antiestrogenic effects in vitro, in vitro systems are incomplete and may not permit an antiestrogenic effect of isoflavones to be observed. Studies involving intact adult animals have not shown that soy feeding increases chemically induced mammary cancer, rather, most show substantial cancer inhibition—generally a 50% reduction in tumor number has been observed.
On a more cautionary note, Hsieh et al (
found that dietary genistein stimulated the growth of MCF–7 cells implanted subcutaneously into ovariectomized nude mice, although growth stimulation was considerably less than that observed for 17ß–estradiol (
. However, there are concerns about whether results from this model can be extrapolated to either premenopausal or postmenopausal women. In contrast with the results of Hsieh et al, Shao et al (9), in a shortterm study, found that in intact mice given 17ß–estradiol subcutaneously, genistein markedly inhibited breast cancer cell growth in vivo.
The complexity of the findings for isoflavones, as shown by these studies (8, 9), was also illustrated by the findings of Foth and Cline (10) in ovariectomized cynomolgus monkeys. They found that in animals not given estradiol, soy feeding produced a nonsignificant increase in mammary cell proliferation but significantly antagonized the stimulatory effects of estradiol on mammary cell proliferation.
Finally, genistein exposure for just a few days during the neonatal and prepubertal periods has been shown to reduce chemically induced mammary cancer in rodents later in life. The proposed mechanism of action seems to involve an estrogenic effect of genistein on mammary tissue, resulting in enhanced mammary tissue development and differentiation. Thus, in young animals, an estrogenic effect of soy on breast tissue may result in a decreased breast cancer risk.
In conclusion, there are insufficient data on which to draw definitive conclusions about the effects of soy consumption on breast tissue in either pre– or postmenopausal women. Epidemiologic data show some support for a protective effect of soy against breast cancer (primarily premenopausal breast cancer) and, importantly, no epidemiologic studies found an increased breast cancer risk associated with soy consumption. However, it is not clear whether these epidemiologic data, which involved primarily Asian women, can be used to assess the effect of adult soy consumption on breast cancer risk in Western populations. The recent findings by McMichael–Phillips et al should serve as a stimulus for much needed research into the effects of soy on breast tissue.
1. McMichael–Phillips DF, Harding C, Morton M, et al. Effects of soyprotein supplementation on epithelial proliferation in the histologi–cally normal human breast. Am J Clin Nutr 1998;68(suppl):1431S–5S.[Abstract]
2. Petrakis NL, Barnes S, King EB, et al. Stimulatory influence of soyprotein isolate on breast fluid secretion in pre– and postmenopausal women. Cancer Epidemiol Biomarkers Prev 1996;5:785–94.[Abstract]
3. Ahnen DJ, Byers T. Proliferation happens. JAMA 1998;280:1095–6.[Free Full Text]
4. Moorghen M, Orde M, Finney KJ, Appleton DR, Watson AJ. Sulin–dac enhances cell proliferation in DMH–treated mouse colonic mucosa. Cell Prolif 1998;31:59–70.[Medline]
5. Zhou JR, Mukherjee P, Gugger ET, Tanaka T, Blackburn GL, Clinton SK. Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis. Cancer Res 1998;58:5231–8.[Abstract/Free Full Text]
6. Willsher PW, Gee JMW, Blamey RW, Nicholson RJ, Robertson JFR. Changes in ER, PgR and pS2 protein during tamoxifen therapy for primary breast cancer. Breast Cancer Res Treat 1994;41:288 (abstr).
7. Xu X, Duncan AM, Merz BE, Kurzer MS. Effects of soy isoflavones on estrogen and phytoestrogen metabolism in premenopausal women. Cancer Epidemiol Biomarkers Prev 1998;7:1101–8.[Abstract/Free Full Text]
8. Hsieh C-Y, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor–positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 1998;58:3833–8.[Abstract/Free Full Text]
9. Shao Z-M, Wu J, Shen Z-Z, Barsky SH. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 1998;58:4851–7.[Abstract/Free Full Text]
10. Foth D, Cline JM. Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. Am J Clin Res 1998;68:1413S–7S.