Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract
    Awarded Grants
    Activation of FOXO Tumor Suppressor for Breast Cancer Therapy and Prevention

    Scientific Abstract:
    BACKGROUND: Our preliminary data indicate that FOXO Forkhead transcription factor suppresses breast cancer cell growth and tumorigenesis in vivo. Since FOXO factors can upregulate tumor necrosis factor-related apoptosis inducing ligand (TRAIL) whose activity can be enhanced by a chemopreventive agent curcumin, a combined treatment with curcumin and novel small molecules that can activate FOXO activity may sensitize breast cancer cells for FOXO-mediated apoptosis and suppress tumorigenesis. OBJECTIVE/HYPOTHESIS: We hypothesize that small molecules that can inhibit the PI3K/Akt and IKK/NF-kB signaling pathways will activate FOXO activity that may synergize curcumin-induced TRAIL activity in killing breast cancer cells. A FDA-approved proteasome inhibitor Bortezomib (PS-341) blocks the IKK/NF-kB pathway; and a novel Akt inhibitor OSU-03012 has been approved by the NCI-RAID (Rapid Access to Intervention Development) program for preclinical toxicology testing. Thus, our goals of this proposal are to investigate the potential therapeutic and preventive effects of the combined treatments with optimal doses of curcumin and OSU-03012 and Bortezomib or other small molecules on breast cancer. SPECIFIC AIMS: We will (1) determine the inhibitory effects of the combination of curcumin and Bortezomib and OSU-03012 on tumorigenicity and tumor growth of human breast cancer cells MDA-MB-231 [ER-] and MCF-7 [ER+] in vitro and in breast tumor xenograft animal models and determine the optimal doses of the combination of these small molecules for chemotherapy of breast cancer; (2) examine the preventive effect of a conditioned diet containing these agents on tumorigenesis of MDA-MB-231 and MCF-7 cells in breast cancer animal models, and determine the optimal doses of these agents for chemoprevention of breast cancer; (3) identify small molecules that increase the transactivating activity of FOXO factors by screening a small-molecule library. We will infect breast cancer cell lines T47D (PTEN-wt) and MDA-MB-468 (PTEN-null) with an adenovirus expressing a secreted alkaline phosphatase (SEAP) gene driven by a promoter containing the FOXO-responsive elements (FRE) and a GFP gene, treat cells with small molecules, and assay for SEAP activity using GFP for expression normalization. POTENTIAL OUTCOMES: The success of the combined treatments with optimal doses of curcumin and Bortezomib and OSU-03012 or other novel nontoxic small molecule-FOXO activators as new anti-cancer tools may provide opportunities for effective therapeutics or strategies for preventing human breast cancer.

    Lay Abstract:
    BACKGROUND: Breast cancer is one of the major causes of death for women in the US; thus, the development of new tools for treatment and prevention is needed. Our preliminary data indicate that FOXO factors can suppress breast cancer cell growth and progression in animal models. Since FOXO factors can activate a cell-death factor (termed TRAIL) whose activity can be enhanced by a natural food product and cancer preventive agent curcumin, a combined treatment with curcumin and small molecules that can increase FOXO activity may suppress breast cancer development and progression. OBJECTIVE/HYPOTHESIS: We hypothesize that small molecules that can inhibit the survival pathways will activate FOXO activity that may synergize curcumin-induced cell killing activity in breast cancer. A FDA-approved proteasome inhibitor Bortezomib (PS-341) blocks the IKK/NF-kB pathway; and a novel Akt inhibitor OSU-03012 has been approved by the NCI-RAID (Rapid Access to Intervention Development) program for preclinical toxicology testing. Thus, our goals of this proposal are to investigate the potential therapeutic and preventive effects of the combined treatments with optimal doses of curcumin and OSU-03012 and Bortezomib or other small molecules on breast cancer. SPECIFIC AIMS: We will (1) determine the inhibitory effects of the combination of curcumin and Bortezomib and OSU-03012 on tumor progression of human breast cancer cells MDA-MB231 and MCF-7 in cell culture and in breast tumor animal models, and determine the optimal doses of the combination of these small molecules for chemotherapy of breast cancer; (2) examine the preventive effect of a conditioned diet [rodent chow containing curcumin and Bortezomib and OSU-03012] on tumor development of MDA-MB231 and MCF-7 cells in breast cancer mouse models, and determine the optimal doses of these agents for chemoprevention of breast cancer; (3) identify small molecules that increase FOXO activity by screening a small-molecule library. We will establish breast cancer cell lines T47D and MDA-MB-468 expressing an enzyme reporter gene under the control of the FOXO-responsive genetic switch, treat cells with small molecules, and assay for the enzyme activity. Novel FOXO-activating small molecules will be selected. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: The success of the combined treatments with optimal doses of curcumin and Bortezomib and OSU-03012 or other novel nontoxic small molecule FOXO-activators as new anti-cancer tools may provide opportunities for effective therapeutics or strategies for preventing human breast cancer.