Recent biomedical technology advances have made it possible to detect breast cancer earlier, but options currently available to help patients with primary breast cancer or women at high risk of breast cancer are very limited. The long-term objective of our project is to identify and develop safe and efficacious agents, such as tocopherols, for prevention of breast cancer. Tocopherols are lipophilic phenolic antioxidants present in significant amounts in vegetable oils, such as soybean, corn, canola and cottonseed. Our laboratory has found that mixed tocopherols containing mainly gamma- and delta-tocopherols prevent an estrogen receptor (ER)- positive breast cancer. Based on our preliminary studies, we hypothesize that gamma- and delta-tocopherols, not alpha-tocopherol (known as a classic vitamin E), prevent breast cancer by inhibiting cell proliferation, inflammation, and oxidative stress, and by regulating receptor signaling pathways including peroxisome proliferator activated receptor (PPAR), ER and Her-2. The major specific aims of this project are to characterize the cancer preventive activities of mixed tocopherols as well as pure isoforms of tocopherols since it is not clear which tocopherol isomers are responsible for chemopreventive effects against breast cancer. Using two distinct preclinical models of breast cancer, we will determine the preventive efficacy of mixed tocopherols as well as the pure alpha-, gamma- and delta-tocopherols in an estrogen receptor (ER)-positive breast cancer and in an ER-negative/Her-2 positive breast cancer. Using immunohistochemistry, ELISA, Western Blot analysis and real time RT-PCR, we will investigate the efficacy and safety of tocopherols in animal models of breast cancer, analyze molecular markers and identify the mechanism of action of tocopherols in vivo. The proposed study will determine (a) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in an ER-positive breast cancer model, (b) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in a Her-2 positive breast cancer model using MMTV-Her-2/neu transgenic mice, and (c) the molecular mechanisms of the tocopherols in receptor signaling pathways such as PPAR, ER and Her-2. This project will provide a thorough understanding of cancer preventive activities of different tocopherols and their combinations, elucidate the detailed molecular mechanisms of cancer preventive actions on tocopherols, and provide fundamental information of tocopherols for future human breast cancer prevention studies.
In year 2008 alone, approximately 180,000 women are being diagnosed with breast cancer in the United States. Although significant advances in technology have made it possible to detect breast cancer earlier, women at high risk or breast cancer patients after mastectomy or lumpectomy have very few options currently available for the prevention of the disease. Our project is focused on the identification of chemopreventive components available in the diet. The major task of the project is to characterize the cancer preventive activities of tocopherol isomers in an estrogen receptor (ER)-positive breast cancer and an ER-negative/Her-2 positive breast cancer. Our study attempts to understand the mechanism of action of pure tocopherol isomers in the prevention of the disease. The successful achievement of this project may contribute to an understanding of how breast cancer can be prevented by tocopherols before it progresses to its terminal invasive and metastatic stages. Since preclinical data are required for further translation studies to develop new agents for prevention and treatment of breast cancer in humans, our proposed study will provide valuable data to benefit patients with primary breast cancer and women at high risk of developing breast cancer. We believe that the outcome from our research will help reduce breast cancer incidence and mortality in the next decade.
| Smolarek, Amanda K; So, Jae Young; Thomas, Paul E et al. (2013) Dietary tocopherols inhibit cell proliferation, regulate expression of ER?, PPAR?, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia. Mol Carcinog 52:514-25 |
| Yang, Chung S; Suh, Nanjoo (2013) Cancer prevention by different forms of tocopherols. Top Curr Chem 329:21-33 |
| Yang, Chung S; Suh, Nanjoo; Kong, Ah-Ng Tony (2012) Does vitamin E prevent or promote cancer? Cancer Prev Res (Phila) 5:701-5 |
| Smolarek, Amanda K; So, Jae Young; Burgess, Brenda et al. (2012) Dietary administration of ?- and ?-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer. Cancer Prev Res (Phila) 5:1310-20 |
| Smolarek, Amanda K; Suh, Nanjoo (2011) Chemopreventive activity of vitamin E in breast cancer: a focus on ?- and ?-tocopherol. Nutrients 3:962-86 |
