DNA-PK plays a central role in transformation of breast epithelial cells following alkylation damage

Abstract

DNA alkylating agents form the first line of cancer chemotherapy. They not only kill cells but also behave as potential carcinogens. MNU, a DNA methylating agent is well known to induce mammary tumours in rodents. However, the mechanism of tumorigenesis is not well understood. Our study reports a novel role played by DNA-PK in methylation damage-induced transformation using three dimensional breast acinar cultures. Here, we report that exposure of breast epithelial cells to MNU led to their inhibition to polarise at the basolateral domain, increased dispersal of Golgi at the apical domain, induction of EMT-like phenotype as well as invasion. This altered Golgi phenotype correlated with impaired intra-cellular trafficking. Inhibition of DNA-PK resulted in almost complete reversal of the altered Golgi phenotype, partial rescue of the polarity defect as well as EMT-like phenotype confirming methylation damage induced activation of DNA-PK as a major mechanism in mediating cellular transformation.