Experiments are proposed to develop mechanism-based, energy restriction-driven interventions that promote the elimination of transformed cells from a tissue by apoptosis. This work is based on our current effort to identify the mechanisms that explain how limiting energy availability by dietary energy restriction (DER) or energy restriction mimetic agents (ERMA) inhibits mammary carcinogenesis and how some clones of transformed cells evade protective activity. The mechanisms that will be investigated include inhibition of autophagy, blocking the switch to aerobic glycolysis, and inhibition of sirtuin-mediated deacetylation. Proof- in-principle experiments are proposed to: 1) determine if chloroquine, an inhibitor of autophagy, enhances the cancer inhibitory activity of energy restriction. We hypothesize that induction of autophagy by energy restriction decreases the cancer inhibitory activity of these interventions by blunting the induction of apoptosis in favor of enhancing cell survival/stress resistance mechanisms;2) investigate whether dichloroacetate, a drug that reverses the switch to aerobic glycolysis observed in cancers (the Warburg effect), can be used to prevent the development of breast cancer and to increase the cancer inhibitory activity of energy restriction. We hypothesize that reversal of aerobic glycolysis will inhibit mammary carcinogenesis and enable energy restriction mediated apoptotic death of transformed cells;and 3) evaluate how the induction of SIRT1 by energy restriction alters the effectiveness of energy restriction in inhibiting mammary carcinogenesis. Our hypothesis is that SIRT1, a class III histone deacetylase that is induced by energy restriction, blunts cancer inhibition mediated by AMPK activation and AKT down regulation. A rapid emergence model for breast cancer will be used to conduct these experiments. When required by the questions being addressed, epithelial cells will be excised from mammary gland and mammary carcinomas using laser capture microdissection. Methods will include transmission electron microscopy, RT-PCR, western blots, reverse phase protein arrays, IHC, and activity assays using fluorescent polarization detection systems. This work has the potential to provide additional new insights about the mechanisms by which energy restriction inhibits mammary carcinogenesis and to define interventions that promote the selective deletion of transformed cells from the breast. If this potential is realized, it would represent a major advance in cancer prevention research and may have applicability to the control of cancer at organ sites in addition to the breast.
DER is the most powerful physiological inhibitor of carcinogenesis identified to date. The mechanistic studies that are now proposed have the potential to provide insights about the specific deficits in cell function that are obligatory for cancer but "re-regulated" by DER. These insights can help us to understand how normal weight individuals avoid cancer as well as explain the increased risk for cancer associated with overweight and obesity. Since DER has direct effects, based on our ongoing work, on at least 4 tumor suppressor genes (LKB1, TSC2, PTEN, and p53) that are misregulated during the development of cancer, it is likely that work such as ours will provide a rationale basis for understanding the organ site specificity of the effects of energetics on the development of cancer. In addition, our work has formally introduced the concept of ERMAs for cancer prevention and we now propose to take this approach to the next level by using DER, and ERMAs, in combination with mechanism specific agents that target autophagy, the Warburg effect, and SIRT1 induction to drive the elimination of transformed cells from mammary tissue. This approach offers the promise of protection against cancer without the need for continuous treatment. The ability to sustain protection against cancer by the selective deletion of transformed cells via enhancing cellular apoptosis would represent a major advance in cancer prevention research and may have applicability to the control of cancer at organ sites in addition to the breast. Similarly, it is possible that some of the concepts proposed could be applied in the therapeutic setting, especially if oncogene expression and/or loss of tumor suppressor function confer sensitivity to the combined treatments that we propose to investigate.
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