Abstract 5725: Differential effects of dietary soy isoflavones on cancer metastasis
Authors: Martinez-Montemayor Michelle M. , Otero-Franqui Elisa , Cubano Luis A. , Flanagan Suranganie Dharmawardhane 
Published: February 2011

Abstract
The role of soy foods in cancer prevention is known but their effects on cancer metastasis remain to be understood. The purpose of this study is to investigate the effects and mechanism of action of dietary soy isoflavones in established carcinomas. This objective was achieved by testing the effect of the individual and combined soy isoflavones on progression of mammary fat pad tumors in nude mice created from green fluorescent protein (GFP) tagged-MDA-MB-435 metastatic cancer cells. Following tumor establishment, mice were orally gavaged with vehicle or soy isoflavones: genistein (10 mg/kg body weight (BW)), daidzein (10 mg/kg BW), or genistein (50%), daidzein (40%), and glycitein (10%) three times per week. Tumor progression was quantified by whole body fluorescence image analysis twice a week followed by microscopic image analysis of excised organs for metastases. Results show that daidzein significantly increased while genistein decreased mammary tumor growth by 38% and 33% respectively. Daidzein increased lung, heart, and kidney metastases while genistein decreased bone and liver metastases. Combined soy isoflavones did not affect primary mammary tumor growth but increased metastasis to all organs tested; i.e. lung, liver, heart, kidney, and bones. Phosphoinositide-3-kinase (PI3-K) pathway real time PCR array analysis on excised tumors demonstrates that genistein significantly downregulated 26% of the genes tested, including Rho GTPases RHOA, RAC1, and CDC42, and their downstream effector PAK1 that are known regulators of cancer cell invasion, and thus, metastasis. Daidzein upregulated 14% of the genes including CCND1, GRB2, MAPK1, JUN, CTNNB1, IRS1, EIF4G1, and GSK3B that regulate proliferation and protein synthesis. Combined soy treatment significantly increased EIF4E and decreased TIRAP expression. Western blotting of mammary tumor extracts following genistein, daidzein, or combined soy isoflavones show that genistein downregulates RhoA, Rac1, and Cdc42 while daidzein upregulates Rac1, GSK3, and eIF4G1 protein expression. Combined soy isoflavones did not show significant differences in expression of Rho GTPases or PAK.
In conclusion, downregulation of Rho GTPases by genistein may reduce mammary tumor growth and metastasis while upregulation of eIF4G and Rac1 by daidzein may increase mammary tumor growth and metastasis. Consumption of soy foods that contain both genistein and daidzein may neutralize their differential effects on primary tumor growth. The increased metastasis but not primary tumor growth in response to combined soy isoflavones indicates that even though dietary soy has been implicated in cancer prevention, caution must be exercised in dietary decisions of soy foods for cancer patients and survivors.
This research was supported by AICR IIG 03-31-06 and NIH/NIGMS SC3GM084824 to SD and NCCR/NIH 2G12RR003035 and S06GM050695 to UCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5725.