Abstract Breast Cancer (BC) is the major prevalent cancer in women in the United States and Puerto Rico with metastatic breast cancer (MBC), often resulting in death. Recent studies have shown that the Akt/mammalian target of rapamycin (mTOR) pathway is a critical signaling cascade that drives MBC. We recently reported that a combined diet of grape polyphenols (resveratrol, quercetin and catechin: RQC) at equimolar concentration is effective at inhibition of mammary tumor growth and metastasis to lung and bones in nude mice. The objective of this study is to investigate a role for RQC in prevention of MBC via inhibition of the Akt/AMPK/mTOR pathway. We found that RQC at 5 μM each inhibits Akt and p70S6 kinase (downstream effector of mTOR) activities in a metastatic variant of the MDA-MB-435 cell line and MDA-MB-231 human BC cells. RQC at 5 μM demonstrated a 2-fold activation of adenosine monophophate-activated protein kinase (AMPK), an endogenous inhibitor of mTOR that acts opposite to Akt. To determine the contribution of individual resveratrol, quercetin, and catechin to the effect of combined RQC on mTOR signaling, MDA-MB-231 cells were treated with RQC at 1, 3 and 9 μM individually and in combination. Results show that at 1 μM, individual or combined RQC did not increase AMPK activity, while at 3 μM, only Quercetin increased AMPK activity. Individual compounds at 1 μM did not affect Akt activity, while combined RQC decreased Akt activity by 20%. At 3 μM, Akt activity is downregulated by all compounds individually and in combination with combined RQC exerting a higher inhibitory effect on Akt activity than individual compounds. In general, the combination of RQC was more efficient at inhibition of the Akt/mTOR pathway than individual compounds. Thus, RQC has the potential to be used alone or in combination with other cancer therapeutics to impede progressive BC. This study was sponsored by the Department of Defense/Breast Cancer Research Program award W81XWH-07-1-0330 to SD and the U54 grant No. CA-096297 to UPR Comprehensive Cancer Center. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2246. doi:1538-7445.AM2012-2246