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Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

¹ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; ² Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee; and ³ Department of Obstetrics and Gynecology, University of Erlangen, Erlangen, Germany

Requests for reprints: Bert W. O'Malley, Department of Cellular and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-6205; Fax: 713-798-5599; E-mail: berto{at}bcm.edu.

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 G₁ 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 G₁ 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. [Cancer Res 2007;67(24):12026–33]

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