Text

theses

Vitamin E is a dietary micronutrient that is recognized as a lipid-soluble antioxidant and suggested to reduce cancer risk. Tocopherol, a member of the vitamin E family, consists of four forms designated as alpha, beta, gamma, and delta. Several large cancer prevention studies with alpha-tocopherol have reported no beneficial results. Recent laboratory studies have suggested that γ-enriched mixed tocopherols (gamma-TmT), gamma-tocopherol and delta-tocopherol inhibit cancer by inhibiting cell proliferation and inducing apoptosis. The purpose of this thesis is to characterize the cancer preventive activities of gamma-TmT and individual (alpha-, delta-, gamma-) tocopherols in the prevention of two subtypes of breast cancer: estrogen receptor (ER) positive and human epidermal growth factor 2 (HER2) positive. As a complex and heterogeneous disease, breast cancer is divided into subtypes such as ER positive, HER2 positive, or basal-like. Animal models are utilized to define etiology of breast cancer and generate new prevention and treatment strategies. In three different animal models of breast cancer, the chemopreventive activities of gamma-TmT or individual tocopherols (alpha, delta or gamma) were assessed. Due to their sensitivity to 17beta-estradiol (E2) to induce mammary hyperplasia, female August Copenhagen Irish (ACI) rats were utilized. Immunohistochemical analysis of the mammary glands revealed a decrease in estrogen receptor alpha (ERalpha) and proliferating cell nuclear antigen (PCNA), while there was an increase in cleaved-caspase 3, peroxisome proliferator activated receptor gamma (PPARgamma), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in gamma-TmT treated rats. In a second animal model, individual delta- and gamma-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats, whereas alpha-tocopherol did not decrease tumor burden. In mammary tumors, markers of cell proliferation (PCNA, PKCalpha), survival (PPARgamma, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by delta- and gamma-tocopherols. However, in the third animal model, administration of individual tocopherols did not prevent HER2/neu-driven tumorigenesis. There were modest effects by gamma-tocopherols on increased tumor latency, but the overall tumor burden was not significantly decreased. In conclusion, delta-tocopherol, gamma-tocopherol and gamma-TmT, but not alpha-tocopherol, have exhibited chemopreventive properties in two estrogen-dependent animal models, but not in transgenic HER2-driven breast cancer.

ETD_4425

Ph.D.

Includes bibliographical references

by Amanda Kathryn Smolarek

http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000067844

doi:10.7282/T3F47MTC

ETD doctoral

The author owns the copyright to this work.