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

C. R. Loehberg; T. Thompson; M. B. Kastan; B. W. O'Malley; M. W. Beckmann

doi:10.1055/s-2008-1079210

Geburtshilfe und Frauenheilkunde, Table of Contents

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

CR Loehberg ¹^,³, T Thompson ¹, MB Kastan ², BW O'Malley ¹, MW Beckmann ³

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

Abstract

Fragestellung: The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. B. W. O'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.

Methodik:

Cell Culture, Short Interfering RNA Transfection, Western Blot Analysis, Flow Cytometry, Animal Model.

Ergebnisse:

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 gland epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, CQ 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 CQ-dependent phosphorylation of the checkpoint protein kinase, ATM, leading to ATM dependent phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, CQ does not induce G1 cell cycle arrest compared to cells isolated from wild-type mice also indicating a p53-dependency.

Schlussfolgerung:

Currently, there are very few agents that have a proven ability to prevent breast cancer and their mechanism of action remains undetermined. Our results indicate that a short prior exposure to CQ may have a preventative application for mammary carcinogenesis. Our studies provide further proof-of-principle for developing prevention therapies based on the modulation of ATM-p53 pathways, whether based on CQ itself or targeting of other steps in the pathway. From a clinical standpoint, however, our results indicate that CQ may have important preventative applications in breast carcinogenesis.