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Supplement: Fifth Internat'l Symposium on the Role of Soy in Preventing and Treating Chronic Disease

Phytoestrogens and Vitamin D Metabolism: A New Concept for the Prevention and Therapy of Colorectal, Prostate, and Mammary Carcinomas^1,2

Heide S. Cross³, Enikö Kállay, Daniel Lechner, Waltraud Gerdenitsch^*, Herman Adlercreutz and H. James Armbrecht^**

Department of Pathophysiology, and ^* Center for Laboratory Animal Care, University of Vienna Medical School, Austria; Institute for Preventive Medicine, Nutrition and Cancer, and Division of Clinical Chemistry, University of Helsinki, Finland; and ^** Geriatric Research, Education, and Clinical Center, St. Louis Veterans Administration Medical Center, St. Louis, MO 63125

³ To whom correspondence should be addressed. E-mail: Heide.Cross{at}akh-wien.ac.at.

Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH)₂-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3–1-hydroxylase) and catabolism (CYP24; 1,25-D3–24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-ß (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05–50 µmol/L. The high concentration of 50 µmol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.

KEY WORDS: • extrarenal vitamin D synthesis • extrarenal vitamin D catabolism • estrogen receptor-ß • genistein • tumor prevention

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