Carcinogenesis Advance Access originally published online on December 10, 2008
Carcinogenesis 2009 30(2):331-339; doi:10.1093/carcin/bgn279
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Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates β-catenin signaling in mammary epithelial cells
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA
* To whom correspondence should be addressed. Arkansas Children’s Nutrition Center, 1120 Marshall Street, Little Rock, AR 72202, USA. Tel: +1 501 364 2849; Fax: +1 501 364 2191; Email: 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 is 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 downregulate 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 downregulation of Wnt-1-induced free β-catenin accumulation in cytosol. Gen inhibition of Wnt-induced c-Myc expression was mimicked by an estrogen receptor (ER)-β-specific but not ER-
-specific agonist and was attenuated with loss of ER-β expression, concordant with decreased E-cadherin expression. E-cadherin small-interfering RNA 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.
Abbreviations: CAS, casein; ER, estrogen receptor; Gen, genistein; LiCl, lithium chloride; scr, scrambled; siRNA, small-interfering RNA
Received September 8, 2008; revised December 4, 2008; accepted December 4, 2008.
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