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Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis.

Publication ,  Journal Article
Loehberg, CR; Thompson, T; Kastan, MB; Maclean, KH; Edwards, DG; Kittrell, FS; Medina, D; Conneely, OM; O'Malley, BW
Published in: Cancer Res
December 15, 2007

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 15, 2007

Volume

67

Issue

24

Start / End Page

12026 / 12033

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • Oncology & Carcinogenesis
  • Mice, Knockout
  • Mice, Inbred BALB C
  • Mice
  • Mammary Neoplasms, Animal
  • Humans
  • Genes, p53
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Loehberg, C. R., Thompson, T., Kastan, M. B., Maclean, K. H., Edwards, D. G., Kittrell, F. S., … O’Malley, B. W. (2007). Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res, 67(24), 12026–12033. https://doi.org/10.1158/0008-5472.CAN-07-3058
Loehberg, Christian R., Tiia Thompson, Michael B. Kastan, Kirsteen H. Maclean, Dean G. Edwards, Frances S. Kittrell, Daniel Medina, Orla M. Conneely, and Bert W. O’Malley. “Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis.Cancer Res 67, no. 24 (December 15, 2007): 12026–33. https://doi.org/10.1158/0008-5472.CAN-07-3058.
Loehberg CR, Thompson T, Kastan MB, Maclean KH, Edwards DG, Kittrell FS, et al. Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res. 2007 Dec 15;67(24):12026–33.
Loehberg, Christian R., et al. “Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis.Cancer Res, vol. 67, no. 24, Dec. 2007, pp. 12026–33. Pubmed, doi:10.1158/0008-5472.CAN-07-3058.
Loehberg CR, Thompson T, Kastan MB, Maclean KH, Edwards DG, Kittrell FS, Medina D, Conneely OM, O’Malley BW. Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res. 2007 Dec 15;67(24):12026–12033.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 15, 2007

Volume

67

Issue

24

Start / End Page

12026 / 12033

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • Oncology & Carcinogenesis
  • Mice, Knockout
  • Mice, Inbred BALB C
  • Mice
  • Mammary Neoplasms, Animal
  • Humans
  • Genes, p53