title: Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis.
abstract: The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. We have previously shown that the tumor-suppressor gene p53 is a potential mediator of hormone (estrogen/progesterone)-induced protection against chemical carcinogen-induced mammary carcinogenesis in animal models. Here, we show for the first time a breast cancer-protective effect of chloroquine in an animal model. Chloroquine significantly reduced the incidence of N-methyl-N-nitrosourea-induced mammary tumors in our animal model similar to estrogen/progesterone treatment. No protection was seen in our BALB/c p53-null mammary epithelium model, indicating a p53 dependency for the chloroquine effect. Using a human nontumorigenic mammary gland epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, chloroquine activates the tumor-suppressor p53 and the p53 downstream target gene p21, resulting in G(1) cell cycle arrest. p53 activation occurs at a posttranslational level via chloroquine-dependent phosphorylation of the checkpoint protein kinase, ataxia telangiectasia-mutated (ATM), leading to ATM-dependent phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, chloroquine does not induce G(1) cell cycle arrest compared with cells isolated from wild-type mice, also indicating a p53 dependency. Our results indicate that a short prior exposure to chloroquine may have a preventative application for mammary carcinogenesis.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Christian R
authors: CR
authors: Loehberg
authors: Tiia
authors: T
authors: Thompson
authors: Michael B
authors: MB
authors: Kastan
authors: Kirsteen H
authors: KH
authors: Maclean
authors: Dean G
authors: DG
authors: Edwards
authors: Frances S
authors: FS
authors: Kittrell
authors: Daniel
authors: D
authors: Medina
authors: Orla M
authors: OM
authors: Conneely
authors: Bert W
authors: BW
authors: O'Malley
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001940:Breast / Q000166:cytology / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002738:Chloroquine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D016158:Genes, p53; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002738:Chloroquine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases