Goals are to investigate the mechanisms of action of VES (vitamin E succinate; RRR-alpha-tocopheryl succinate), a potent inducer of apoptosis in human breast cancer cells but not normal mammary epithelial cells. The applicant's studies show that VES can restore both transforming growth factor-beta (TGF-beta) and Fas/CD95 impaired anti-proliferative and death signaling in human breast cancer cells that are resistant to these two important cell homeostatic signaling pathways. In this competing continuation application the applicant proposes to investigate critical signaling events involved in VES initiated apoptosis in human MDA-MB-435 breast cancer cells. Normal human mammary epithelial cells (HMECs) and immortalized, non-tumorigenic human mammary epithelial MCF-10A cells which are insensitive to VES induced apoptosis but responsive to both TGF-beta and Fas induced cell fates will be studied for comparative purposes.
Aim 1 will characterize components of the TGF-beta signal transduction pathway contributing to VES-induced apoptosis.
Aim 2 will characterize Fas signal transduction events involved in VES induced apoptosis.
Aim 3 will investigate the decision phase of apoptosis in VES treated cells with emphasis on Bax and mitochondrial mediated events that produce downstream execution phase mediators. Comparisons between VES and ligand (TGF-beta1 and anti-Fas agonistic antibody) mediated events in MDA-MB-435, HMECs and MCF-10A cells will address the molecular basis of VES's selective ability to induce apoptosis in cancer cells but not in normal or immortalized but non-tumorigenic cells. Expectations are that data generated will increase basic knowledge about TGF-beta and Fas signaling in normal and cancer cells and will provide a better understanding of how VES, a potent pro-apoptotic agent, induces cell death. Part of the significance of these mechanistic studies lies in the potential use of agents like VES for chemotherapy of human breast cancer. This possibility has been strengthened by the recent demonstration that a VES ether analog is a potent, orally active chemotherapeutic agent in a preclinical xenograft model of human breast cancer. Another aspect of the significance of these type studies lies in the belief that better understanding of signaling events will lead to the identification of critical intracellular signal transduction molecules which can be targeted for design of mechanism-based drugs to achieve improved cancer cell killing.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA059739-07
Application #
6194618
Study Section
Special Emphasis Panel (ZRG1-ET-2 (01))
Program Officer
Perloff, Marjorie
Project Start
1994-08-01
Project End
2005-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
7
Fiscal Year
2000
Total Cost
$270,000
Indirect Cost
Name
University of Texas Austin
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
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Yu, Weiping; Tiwary, Richa; Li, Jing et al. (2010) ýý-TEA induces apoptosis of human breast cancer cells via activation of TRAIL/DR5 death receptor pathway. Mol Carcinog 49:964-73
Yu, Weiping; Jia, Li; Park, Sook-Kyung et al. (2009) Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol. Mol Nutr Food Res 53:1573-81
Latimer, Paul; Menchaca, Marla; Snyder, Rachel M et al. (2009) Aerosol delivery of liposomal formulated paclitaxel and vitamin E analog reduces murine mammary tumor burden and metastases. Exp Biol Med (Maywood) 234:1244-52
Yu, Weiping; Jia, Li; Wang, Pei et al. (2008) In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms. Mol Nutr Food Res 52:447-56
Wang, Pei; Yu, Weiping; Hu, Zhanzhi et al. (2008) Involvement of JNK/p73/NOXA in vitamin E analog-induced apoptosis of human breast cancer cells. Mol Carcinog 47:436-45
Riedel, Shelley B; Fischer, Susan M; Sanders, Bob G et al. (2008) Vitamin E analog, alpha-tocopherol ether-linked acetic acid analog, alone and in combination with celecoxib, reduces multiplicity of ultraviolet-induced skin cancers in mice. Anticancer Drugs 19:175-81
Snyder, Rachel M; Yu, Weiping; Jia, Li et al. (2008) Vitamin E analog alpha-TEA, methylseleninic acid, and trans-resveratrol in combination synergistically inhibit human breast cancer cell growth. Nutr Cancer 60:401-11
Yu, Weiping; Park, Sook-Kyung; Jia, Li et al. (2008) RRR-gamma-tocopherol induces human breast cancer cells to undergo apoptosis via death receptor 5 (DR5)-mediated apoptotic signaling. Cancer Lett 259:165-76
Jia, Li; Yu, Weiping; Wang, Pei et al. (2008) In vivo and in vitro studies of anticancer actions of alpha-TEA for human prostate cancer cells. Prostate 68:849-60

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