Dietary monoterpenes derived from plant essential oils have been shown to prevent DMBA-, NMU- and retroviral-ras-initiated rat mammary cancer at various stages of carcinogenesis. Dietary terpenes also induce the complete regression of the majority of large, established mammary carcinomas with an excellent therapeutic ratio. Several important cellular, metabolic and molecular effects have been shown to be associated with prevention and therapy of mammary cancer by terpenes. These findings have led directly to on-going and planned cancer clinical trials.
Aim 1 further characterizes and evaluates the importance of several potential mechanisms underlying cancer prevention at the promotion/progression stage as well as cancer treatment by terpenes. The occurrence and relevance of terpene inhibition of protein isoprenylation and ubiquinone synthesis in vivo will be studied. The ability of terpenes to induce differentiation will be mechanistically addressed in a neuroblastoma cell culture model by exploring the cAMP signaling pathway. Positive findings will be evaluated in terpene-treated mammary carcinomas. The role of recently identified overexpressed proteins, including the mannose-6-phosphate/IGFII receptor and TGFbeta, in carcinomas induced to regress by terpenes will be evaluated for their role in the regression process. In addition, genes differentially expressed in terpene-induced carcinoma regressions will be isolated by a recently developed, integrated and improved subtractive hybridization/differential display method and then characterized.
Aim 2 focuses on providing guidance for future clinical trial designs by evaluating the ability of terpenes to prevent and treat neu-associated DCIS and mammary carcinomas. The therapeutic effects of combining terpenes and HMG-CoA reductase inhibitors will also be evaluated. Accomplishment of these aims will both contribute to our understanding of the etiology and biology of breast cancer and facilitate on-going and future clinical trials of monoterpenes for their prevention and treatment of cancer.
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