The anti-tumor activity of rapamycin is compromised by the 
feedback-loop-relevant hyperactive PI3K and ERK-MAPK pathway signaling. In 
breast cancer cells treated with rapamycin, we observed a moderate increase of 
AKT phosphorylation (P-AKT) in a rapamycin resistant cell line, MDA-MB-231, as 
well as a slight increase of P-AKT in a rapamycin sensitive cell line, MCF-7. We 
found that resveratrol, a natural phytoalexin, suppressed the phosphorylation 
and activation of the PI3K/AKT pathway in all the three breast cancer cell lines 
that we tested. It also had a weak inhibitory effect on the activation of the 
mTOR/p70S6K pathway in two cell lines expressing wildtype PTEN, MCF-7 and 
MDA-MB-231. The combined use of resveratrol and rapamycin resulted in modest 
additive inhibitory effects on the growth of breast cancer cells, mainly through 
suppressing rapamycin-induced AKT activation. We, therefore, reveal a novel 
combination whereby resveratrol potentiates the growth inhibitory effect of 
rapamycin, with the added benefit of preventing eventual resistance to 
rapamycin, likely by suppressing AKT signaling. We also present data herein that 
PTEN is an important contributor to resveratrol's growth suppressive effects and 
its potentiation of rapamycin in this therapeutic scenario, as resveratrol's 
suppression of rapamycin-mediated induction of P-AKT is both PTEN-dependent and 
-independent. Thus, the resveratrol-rapamycin combination may have therapeutic 
value in treating breast cancer and perhaps other processes where mTOR is 
activated.