IGF-1, DNA REPAIR AND NEOPLASIA

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IGF-1, DNA REPAIR AND NEOPLASIA

in summary

There is growing evidence suggesting that the evolutionarily conserved insulin-like growth factor-1 (IGF-1) signaling pathway regulates both life span and development of age-related diseases, including cancer.

the details

Funded by OK-INBRE

There is growing evidence suggesting that the evolutionarily conserved insulin-like growth factor-1 (IGF-1) signaling pathway regulates both life span and development of age-related diseases, including cancer. Population studies demonstrate statistical connection between serum IGF-1 levels and the relative risk of developing cancers. A breakthrough longitudinal study in Ecuadorian individuals who carry mutations in the GHR gene demonstrate that severe lifelong IGF-1 deficiency results in zero cancer incidence. Recent studies by our laboratories and by others have uncovered prima facie evidence suggesting that peripubertal levels of GH/IGF-1 in experimental animals are especially important in determining susceptibility to cancer later in life. The central hypothesis is that IGF-1 during a critical development window activates an epigenetic switch within cells resulting in permanent modifications in the DNA repair machinery that regulate genomic stability throughout the lifespan. We predict that alterations of the timing, magnitude and/or duration of peripubertal levels of IGF-1 influence cellular DNA repair pathways, promoting genomic stability and preventing cancer development. Aims: 1) Determine the contribution of the peripubertal IGF-1 surge to late-life susceptibility to tumor induction in mice. We postulate, on the basis of preliminary data, that delays in timing and/or decreases in the magnitude of the peripubertal IGF-1 surge decreases susceptibility to DMBA-induced mammary carcinogenesis. 2): Determine the impact of the peripubertal increase in IGF-1 on cellular DNA repair machinery. Our hypothesis, based on our preliminary studies, is that shifts in the timing and/or decreases in the magnitude of the peripubertal IGF-1 surge increase genomic stability by increasing cellular DNA repair capacity. 3): Determine the epigenetic mechanisms induced by the peripubertal IGF-1 surge that impact cellular DNA repair machinery. We postulate that the peripubertal IGF-1 surge, through epigenetic regulation, elicits persistent changes in expression of DNA repair genes. Successful completion of these studies will establish the causal link between the IGF-1 levels and susceptibility to cancer induction, define the critical development window for the effects of IGF-1 and assess whether these effects are mediated through epigenetic regulation. Our studies have relevance to the goals of OK-INBRE program since we will establish a new line of cancer research at the Reynolds Oklahoma Center on Aging, promoting collaboration with the Peggy and Charles Stephenson Cancer Center that will result in competitive NIH grant applications within one year.