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Soy Isoflavones, Estrogens and Growth Factor Signaling

By Stephen Barnes, Ph.D. and Helen Kim, Ph.D.

Soybeans are unique among beans because they contain compounds called isoflavones. Because these molecules have structures very similar to the body's natural estrogens (hence the name plant- or phyto-estrogens), major research efforts are directed at understanding what isoflavones do in our bodies when we eat soy.

Estrogens

Estrogens are hormones that our bodies make and require for normal growth and development, and to maintain good adult health not only in women, but also in men. Estrogens are essential for the female reproductive system, but they are also important for the bones, the heart, and possibly the brain.

For women faced with menopause (and loss of estrogens), how to replace estrogens is a major issue. In standard hormone replacement therapy (HRT), the combination of estrogens with a synthetic progesterone prevents osteoporosis - it also largely overcomes the increased risk of uterine cancer from using estrogens alone (1). However, combination HRT is less effective than estrogens alone in protecting against heart disease, and may slightly increase breast cancer risk (2). So, on the one hand, estrogens are good; however, dealing with their replacement is a complex issue.

How do estrogens work? They complex with proteins called estrogen receptors (ERs). These complexes "dock" at sites (response elements) within selected genes in the cell's nucleus, switching those genes on or off. This switching makes cells proliferate (like breast growth during puberty) or causes them to differentiate and make special products (for example, milk following pregnancy). For many years, only a single ER was known, ER alpha. Now another ER, ER beta, has been found (3), and predominates in certain estrogen-responsive tissues, such as bone and the bladder (4). This explains why estrogens can have beneficial effects in bone and can control urinary incontinence, even though for years ER alpha could not be detected in either bone or the bladder.

Soy Isoflavones

How do soy isoflavones fit into estrogen action? Genistein, the most abundant isoflavone in soybeans, binds only weakly with ER alpha, but complexes with ER beta almost as well as estrogen does (5). This probaby explains genistein's ability to prevent bone loss in ovariectomized rats (6). The predominance of ER beta in the cardiovascular system suggests that soy isoflavones may be partly responsible for the lower incidence of heart disease in soy-consuming countries.

And what about cancer? In countries (mostly Southeast Asia) where soy consumption is high, the incidence of breast, prostate and uterine cancer is substantially lower than in the USA (7). Moreover, in a group of caucasian (Australian) women, those whose diets included higher amounts of isoflavones and other phytoestrogens had a lowered incidence of breast cancer (8). Interestingly, the intake of soy in these women (derived from their urinary isoflavonoid output rate) was less than one serving per day. Does this mean that eating soy and its isoflavones protects us from cancer? Conclusive answers cannot be given at this time, since the observed beneficial effects could be the result of associated dietary/lifestyle factors. It should also be noted that using concentrated isoflavone preparations (in pill form, for example) extracted from the soybean leaves behind the rest of the phytochemicals in soy foods that have health benefits. This may have effects that are impossible to predict at this point.

Isoflavones and Growth Factor Signaling

Many chronic human diseases involve defects in growth factor action. Growth factors are molecules that regulate the growth (proliferation) of cells. They can be released from cells in response to estrogen, and affect neighboring cells. When growth factors bind to their receptors (usually located straddling the cell's membrane), the part of the receptor inside the cell issues a signal to the rest of the cell, much like a doorbell at the entrance to a house. You can imagine how disruptive it would be if someone changed the doorbell from a soft sound to a really loud one. On the other hand, if the doorbell broke, you wouldn't know if anyone was at the door.

A significant advance in our understanding of the health benefits of soy comes from its use in treatment of the Osler-Weber-Rendu (OWR) syndrome. OWR is a hereditary disease where patients suffer multiple episodes of nose bleeds (in some as many as 3-6 a day) (9). Although not life-threatening, the loss of blood (which can also occur elsewhere in the body) often requires blood transfusions to maintain normal hematocrit levels. In an initial study at Yale University, certain OWR patients on a soy protein diet containing the isoflavones experienced an almost complete cessation of bleeding (10). This is all the more fascinating because genetic mutations that cause OWR produce defects in proteins involved in a signaling pathway initiated by transforming growth factor beta (TGFb) (11). How the actions of soy isoflavones interface with TGFb signaling remains to be elucidated, but in view of the data, we suggest that abnormalities in TGFb signaling may be at the crux of certain soy responsive diseases, including cancer, heart disease and osteoporosis (12). If so, isoflavones may be better understood by their effects on growth factors than for their apparent similarity to estrogens.

References

(1) Beresford SA. Weiss NS. Voigt LF. McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestation therapy in postmenopausal women. Lancet 1997;349:458-61.

(2) Beral V, Bull D, Doll R, Key T, Peto R, Reeves G, Calle EE, Heath CW, Coates RJ, Liff JM, Franceschi S, Talamini R, Chantarakul N, Koetsawang S, Rachawat D, Morabia A, Schuman L, Stewart W, Szklo M, Bain C, Schofield F, Siskind V, Band P, Coldman AJ, Gallagher RP, et al. Breast cancer and hormone replacement therapy - collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-1059.

(3) Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996;93:5925-5930.

(4) Onoe Y, Miyaura C, Ohta H, Nozawa S, Suda T. Expression of estrogen receptor beta in rat bone. Endocrinology, 1997;138:4509-4512.

(5) Kuiper GGJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology, 1997;138:863-870.

(6) Blair H, Jordan SE, Peterson TG, Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J Cell Biochem, 1996;61:629-637.

(7) Greenwald P: Principles of Cancer Prevention. Diet and Nutrition. In: DeVita VT Jr, Hellman S, Rosenberg SA (eds): "Cancer: Principles and Practice of Oncology", 3rd Edition, Philadelphia, JB Lippincott, 1989, pp 167-180.

(8) Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto oestrogens and breast cancer. Lancet, 1997;350(9083):990-994.

(9) Guttmacher AE, Marchuk DA, White RI, Jr. Hereditary hemorrhagic telangiectasia. New Engl J Med, 1995;333:918-24.

(10) Korzenik JR, Barnes S, White RI, Jr. A pilot study of soy protein isolat in the treatment of hereditary hemorrhagic telangiectasia (HHT): possible efficacy in HHT associated epistaxis, gastrointestinal hemorrhage and migraine. Am J Clin Nutr, accepted for publication.

(11) McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary hemorrhagic telangiectasia type 1. Nature Genetics. 1994;8:345-51.

(12) Kim H, Peterson TG, Barnes S. Mechanisms of action of the soy isoflavone genistein: emerging role of its effects through transforming growth factor beta signaling pathways. Am J Clin Nutr, accepted for publication.

About the authors

Stephen Barnes, Ph.D. is professor in the Department of Pharmacology & Toxicology, University of Alabama at Birmingham. He is also director of the UAB Comprehensive Cancer Center Mass Spectrometry Care Facility. He obtained his Ph.D. in biochemistry in 1970 from the Imperial College of Science and Technology, University of London.

Helen Kim, Ph.D. is research associate professor in the Dept. of Pharmacology & Toxicology at the University of Alabama at Birmingham. Her Ph.D. in biophysics was obtained from the University of Virginia in 1983.

Reprinted with permission from The Soy Connection newsletter, Volume 6, No. 2, Spring 1998. More information about the newsletter can be obtained by writing to:

Editor, The Soy Connection
P.O. Box 237
Jefferson City, MO 65102

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Indiana Soybean Board

 



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