To investigate the effects soy
isoflavones in established
cancers, the role of
genistein,
daidzein, and combined soy
isoflavones was studied on progression of subcutaneous
tumors in nude mice created from
green fluorescent protein (GFP) tagged-MDA-MB-435 cells. Following
tumor establishment, mice were gavaged with vehicle or
genistein or
daidzein at 10 mg/kg
body weight (BW) or a combination of
genistein (10 mg/kg BW),
daidzein (9 mg/kg BW), and
glycitein (1 mg/kg BW) three times per week.
Tumor progression was quantified by whole body fluorescence image analysis followed by microscopic image analysis of excised organs for
metastases. Results show that
daidzein increased while
genistein decreased mammary
tumor growth by 38 and 33% respectively, compared to vehicle.
Daidzein increased lung and heart
metastases while
genistein decreased bone and liver
metastases. Combined soy
isoflavones did not affect primary
tumor growth but increased
metastasis to all organs tested, which include lung, liver, heart, kidney, and bones. Phosphoinositide-3-kinase (PI3-K) pathway real time PCR array analysis and western blotting of excised
tumors demonstrate that
genistein significantly downregulated 10/84 genes, including the
Rho GTPases RHOA, RAC1, and CDC42 and their effector PAK1.
Daidzein significantly upregulated 9/84 genes that regulate proliferation and
protein synthesis including EIF4G1,
eIF4E, and
survivin protein levels. Combined soy treatment significantly increased gene and
protein levels of
EIF4E and decreased TIRAP gene expression. Differential regulation of
Rho GTPases,
initiation factors, and
survivin may account for the disparate responses of breast
cancers to
genistein and
daidzein diets. This study indicates that consumption of soy foods may increase
metastasis.