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    Awarded Grants
    Type-I and Type-II Anti-Tumor-Promotion Agents: Combinations of Tamoxifen, a New Retinoid, and Moderate Dietary Restriction in the Prevention of Experimental Breast Cancers

    Scientific Abstract:
    TITLE OF PROJECT: Type-I and type-II anti-tumor-promotion agents: Combinations of tamoxifen, a new retinoid, and moderate dietary restriction in the prevention of experimental breast cancers BACKGROUND: Previous work by this investigator has suggested that anti-tumor-promotion agents can be classified into two types: type I and type II. Type-I agents induce what we refer to as “type-I apoptosis” by downregulating cyclin D1 (a G1-phase cyclin) and cyclin A (an S-phase cyclin), and upregulating p27Kip1 (a cyclin-dependent kinase inhibitor). In contrast, type-II agents induce what we refer to as “type-II apoptosis” by upregulating cyclin D1, and downregulating p27Kip1 and cyclin A. Examples of type-I agents include dexamethasone, corticosterone, and, possibly, dietary caloric restriction. Examples of type-II agents include all-trans-retinoic acid and 9-cis-retinoic acid. Since type-I and type-II anti-promotion agents act in opposite directions in terms of cyclin D1 and p27Kip1, any combination of type-I and type-II agents is likely to result in partial or total cancellation of their anti-promotion effects. In contrast, combination of two or more anti-promotion agents of the same type should produce additive or even synergistic effects. It becomes essential therefore to be able to categorize anti-promotion agents as type I or type II. OBJECTIVE/HYPOTHESIS: The objective of the proposed study is to test the hypothesis that (1) tamoxifen and a new retinoid 9-cis-UAB30 (9cUAB30) are type-II anti-tumor-promotion agents and (2) moderate dietary restriction is a type-I anti-tumor-promotion agent. SPECIFIC AIMS/STUDY DESIGN: To test this hypothesis, we will use the N-methyl-N-nitrosourea (MNU)-induced rat mammary cancer model in vivo and determine the effects of various combinations of tamoxifen, 9cUAB30 and moderate dietary restriction on the expression and molecular control of G1 cell cycle regulatory proteins and apoptosis in the mammary adenocarcinomas and normal mammary epithelial cells. The FIRST AIM is to determine the expression and molecular control of G1 cell cycle regulatory proteins by performing (a) conventional, non-proteomic analyses of cyclin D1-, E-, and A-containing complexes using nearest-neighbor approaches (immunoprecipitation or pulling down complexes using affinity-tagged proteins) and (b) proteomic analyses of the complexes using nearest-neighbor and subcellular approaches. The SECOND AIM is to investigate the type of apoptosis that would be induced by various combinations of tamoxifen, 9cUAB30 and moderate dietary restriction. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: We believe that anti-tumor-promotion agents could be classified into two types: type I and type II. This concept has great significance for understanding the often puzzling behavior of complex mixtures of natural substances, such as found in foods, when their effects on breast cancer prevention are considered. The second significant benefit of the proposed study stems from the practical application of this concept of type I and type II anti-tumor-promotion agents. The proposed study addresses the following important question: What combinations of the three - tamoxifen, a vitamin A analog (9cUAB30), and moderate dietary restriction - have additive (i.e. beneficial) or antagonistic (i.e. detrimental) effects on the prevention of breast cancers? We should promote those combinations that have beneficial effects and avoid those that have detrimental effects.

    Lay Abstract:
    TITLE OF PROJECT: Type-I and type-II anti-tumor-promotion agents: Combinations of tamoxifen, a new retinoid, and moderate dietary restriction in the prevention of experimental breast cancers Recently we have completed extensive studies on the processes that convert a normal cell into a cancerous one. We used a chemically-induced rat mammary cancer model for studies in live animals and mouse epidermal cell lines in culture. These studies have allowed us to distinguish two classes of cancer-preventive agents, which we call type-I and type-II agents. The importance of this is that cancer-preventing activity seems to disappear whenever type-I and type-II agents are administered together. On the other hand, administering together two or more agents of the same type seems to potentiate their beneficial effect. This concept has great significance for understanding the often puzzling behavior of complex mixtures of natural substances, such as found in foods, when their effects on cancer prevention are considered. The objective of the proposed study is to apply this concept of type-I and type-II agents to the combinations of tamoxifen, a new vitamin A analog and moderate dietary restriction in the prevention of chemically-induced rat mammary cancers. We already know that tamoxifen and/or vitamin A prevent breast cancers. We also know that moderate dietary or caloric restriction prevents breast cancers. The proposed study addresses the following important question: What combinations of the three - tamoxifen, the new vitamin A analog and moderate dietary restriction - have additive (i.e. beneficial) or antagonistic (i.e. detrimental) effects on the prevention of breast cancers? We should promote those combinations that have beneficial effects and avoid those that have detrimental effects. We will also look more closely at the molecular mechanisms that govern the division and death of cells since these mechanisms underlie the cancer-preventive activities of both type-I and type-II cancer-preventive agents.