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Carcinogenesis Advance Access published online on December 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn279
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Soy Isoflavone Genistein Up-regulates Epithelial Adhesion Molecule E-Cadherin Expression and Attenuates β-catenin Signaling in Mammary Epithelial Cells

Ying Su and Rosalia C.M. Simmen

Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, and Arkansas Children's Nutrition Center, Little Rock, AR 72202

Requests for reprints: Rosalia C.M. Simmen, Ph.D., Arkansas Children's Nutrition Center, 1120 Marshall St., Little Rock, AR 72201; Phone: 501-364-2849; Fax: 501-364-2191; E-mail: simmenrosalia{at}uams.edu

Breast cancer risk is highly modifiable by diet, however, mechanisms underlying dietary protection against mammary tumorigenesis remain poorly understood. A proportion of breast carcinomas are associated with deregulation of β-catenin stability and amplification of c-Myc expression. We recently showed that dietary exposure to the soy isoflavone genistein (Gen) inhibited Wnt transduction in rat mammary epithelial cells in vivo. Here we explored the role of Gen on cell adhesion protein E-cadherin expression to down-regulate β-catenin proto-oncogene function. In mammary glands of female rats exposed to dietary Gen, E-cadherin and β-catenin protein levels were increased, concurrent with higher β-casein gene expression. In HC11 mouse mammary epithelial cells, Gen diminished basal and Wnt-1-induced cell proliferation and attenuated Wnt-1 targets c-Myc and Cyclin D1 expression. Whereas Gen had no effect on E-cadherin transcript levels, the abundance of membrane E-cadherin protein and of E-cadherin/β-catenin adhesion complex was increased by Gen, attendant with down-regulation of Wnt-1-induced free β-catenin accumulation in cytosol. Gen inhibition of Wnt-induced c-Myc expression was mimicked by an ER-β but not ER-{alpha} specific agonist and was attenuated with loss of ER-β expression, concordant with decreased E-cadherin expression. E-cadherin siRNA targeting eliminated Gen inhibition of Wnt-stimulated c-Myc expression and promoted Gen induction of basal c-Myc transcript levels and subsequent proliferation. Our studies identify E-cadherin as a Gen cellular target and demonstrate that the dichotomy in mammary epithelial response to Gen may be a function of cellular E-cadherin expression.

Key Words: genistein • β-catenin • E-cadherin • mammary epithelial • Wnt • breast cancer

Received September 8, 2008; revised December 4, 2008; accepted December 4, 2008.


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