ATM and p53 are potential mediators of Chloroquine-induced resistance to mammary carcinogenesis

The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. Orsquor;Malley et al. have previously shown that the tumor suppressor gene p53 is a potential mediator of hormone estrogen/progesterone (E/P)-induced protection against chemical carcinogen-induced mammary carcinogenesis in animal models. Here we demonstrate for the first time a breast cancer protective effect of Chloroquine (CQ) in an animal model. CQ significantly reduced the incidence of N-methyl-N-nitrosourea (NMU)-induced mammary tumors in our animal model similar to E/P-treatment. No protection was seen in our BALB/c p53-null mammary epithelium model indicating a p53-dependency for the CQ effect. Using a human non-tumorigenic mammary epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, CQ activates the tumor-suppressors p53 and p21, resulting in G1 cell cycle arrest. p53 activation occurs at a posttranslational level via CQ-dependent phosphorylation of the protein kinase, ATM, leading to phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, CQ does not induce G1 cell cycle arrest compared to wild-type cells also indicating a p53-dependency. Our results indicate that a short prior exposure to CQ may have a preventative application for mammary carcinogenesis. Our studies provide further proof-of-principlefor developing prevention therapies based on the modulationof ATM-p53 pathways, whether based on CQ itself ortargeting of other steps in the pathway. From a clinical standpoint, however, our results indicate that CQ may have importantpreventative applications in breast carcinogenesis.

animal model - breast cancer - chloroquine - prevention