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Low Concentrations of the Soy Phytoestrogen Genistein Induce Proteinase Inhibitor 9 and Block Killing of Breast Cancer Cells by Immune Cells

Departments of Biochemistry (X.J., N.M.P., D.J.S.) and Food Science and Human Nutrition (Y.L., J.X., W.G.H.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: David J. Shapiro, Department of Biochemistry, University of Illinois, 413 RAL, 600 South Mathews Avenue, Urbana, Illinois 61801. E-mail: djshapir{at}uiuc.edu.

The risks and benefits of diets and supplements containing the estrogenic soy isoflavone genistein are not well established. We report that 10 nM genistein potently induces the granzyme B inhibitor, proteinase inhibitor 9 (PI-9) in MCF-7 human breast cancer cells. By inducing PI-9, genistein inhibits the ability of human natural killer (NK) cells to lyse the target breast cancer cells. In ERHA cells, stably transfected MCF-7 cells, which contain elevated levels of estrogen receptor- (ER), 100 pM genistein or 17β-estradiol potently induce PI-9 and prevent NK cells from killing the target breast cancer cells. The concentrations of genistein that fully induce PI-9 in MCF-7 cells, and in ERHA cells, are far lower than those previously reported to elicit estrogenic responses through ER. Because 4-hydroxytamoxifen, raloxifene, and ICI 182,780/Faslodex all block genistein induction of PI-9 and elevated levels of ER enhance induction of PI-9, genistein acts via ER to induce PI-9. Increasing levels of ER in breast cancer cells results in a progressive increase in induction of PI-9 by genistein and in the cell’s ability to evade killing by NK cells. Moderate levels of dietary genistein and soy flour effectively induce PI-9 in human breast cancers grown in ovariectomized athymic mice. A significant population consumes levels of genistein in soy products that may be high enough to induce PI-9, perhaps potentiating the survival of some preexisting breast cancers by enabling them to evade immunosurveillance.