ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts

Abstract

The ATR protein kinase is a master regulator of the cellular responses to DNAdamage and replication stresses. Despite these crucial physiological roles, theimplication of ATR in human carcinogenesis remains elusive. We have shown here thatthe ATR level is reduced in most cancer-associated fibroblasts (CAFs) as compared totheir adjacent normal counterparts. Importantly, specific ATR knockdown activatedbreast fibroblasts, and enhanced their paracrine pro-carcinogenic effects via strongincrease in the expression/secretion of SDF-1 and IL-6. Furthermore, ATR-deficientfibroblasts enhanced tumor growth and aggressiveness in orthotopic breast tumorxenografts. On the other hand, ectopic expression of ATR suppressed the expression/secretion of several cancer-promoting proteins such as IL-6, TGF-β1 and SDF-1,and inhibited the migration and invasion capacities of breast myofibroblast cells.Furthermore, ATR up-regulation in active breast fibroblasts reduced their paracrinepro-migratory/-invasive effects on breast cancer cells. Interestingly, the cancerpromoting effects of ATR-deficient cells were repressed by ectopic expression of theATR effector p53. These results indicate that ATR is a major target of cancer cells inbreast fibroblasts wherein this protein kinase represses both autocrine and paracrinepro-carcinogenic effects. This indicates that the ATR status in these cells could be ofgreat prognostic/diagnostic values.