Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of
cancer, including highly prevalent UV-associated skin
carcinomas. The mechanism by which
caffeine protects against
skin cancer is unknown.
Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint
kinase activated by
DNA stresses and is one of several targets of
caffeine. Suppression of ATR, or its downstream target
checkpoint kinase 1 (Chk1), selectively sensitizes
DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as
ataxia telangiectasia mutated (ATM) and BRCA1, promotes
cancer. To determine the effect of replication checkpoint inhibition on
carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc(-/-). Unlike
caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained
tumor-free for significantly longer (P = 0.003) and had 69% fewer
tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin
carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.