Inhibition of Dimethylbenz[a]anthracene-Induced Breast Tumors in Rats by Soy Protein is Mediated by Downregulation of MAPK/AP-1 Signaling

Abstract

We reported earlier that replacement of casein by soy protein in the diets of rats exposed to the carcinogen, dimethylbenz[a]anthracene (DMBA), not only delayed the initiation of breast tumor but also had a protective effect against the development of aggressive tumor. The aim of this study was to elucidate the molecular mechanism by which soy protein offers these beneficial effects. Tumor was developed by gavage administration of single dose of 80 mg/kg of DMBA into 50-day old female rats, maintained on a standard AIN-76A diet containing either casein or soy protein. After ~120 days of DMBA administration, we evaluated the role of MAPK phosphorylation and subsequent AP-1 activation on the differential effects of soy protein and casein on the development of aggressiveness and progression of DMBA-induced breast tumor and determined if soy protein controls MMP-9 and uPAR expression by modifying AP-1 activity. The present study demonstrates that the beneficial effect of soy protein in breast tumor development is mediated by control of MAPK/AP-1 signaling. It is concluded that deactivation of MAPK pathway lead to down-regulation of the AP-1 activation which in turn down regulates the target gene and may be responsible for controlling breast tumor aggressiveness. Thus, it is suggested that MAPKs (ERK, p38 and JNK), MMP-9 and uPAR may be a potential target for anticancer therapy inhibiting tumor vasculature and invasion stimulated by tumor-associated stroma, and regulating the target gene and may be responsible for the beneficial effects of soy protein.