Carcinogenesis Advance Access published online on April 8, 2004
Carcinogenesis, doi:10.1093/carcin/bgh160
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
* Corresponding author. E-mail: fjgonz{at}helix.nih.gov.
Received 5 December 2003
; revised 19 March 2004
; accepted 31 March 2004
Peroxisome proliferator activated receptor
PPARPPAR
influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis
2 Veterinary and Tumor Pathology Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
3 Department of Veterinary Science and Center for Molecular Toxicology, The Pennsylvania State University, University Park, PA 16802, USA
(PPAR), a member of the nuclear receptor superfamily, plays a role in adipocyte differentiation, type II diabetes, macrophage response to inflammation, and is suggested to influence carcinogen-induced colon cancer. Studies done in vitro and in vivo also revealed that PPAR ligands may promote differentiation and/or regression of mammary tumors. To directly evaluate the role of PPAR in mammary carcinogenesis, PPAR wild-type (+/+) or heterozygous (+/-) mice were administered 1 mg DMBA by gavage once a week for 6 weeks and followed for a total of 25 weeks. Compared to congenic PPAR(+/+) littermate controls, PPAR(+/-) mice had early evidence for increased susceptibility to DMBA-mediated carcinogenesis based on a 1.6-fold increase in the percentage of mice with skin papillomas, as well as a 1.7-fold increase in the numbers of skin papillomas per mouse (p<0.05). Similarly, PPAR(+/-) mice also had a 1.5-fold decreased survival rate (p=0.059), and a 1.7-fold increased incidence of total tumors per mouse (p<0.01). Moreover, PPAR(+/-) mice had an almost 3-fold increase in mammary adenocarcinomas (p<0.05), an over 3-fold increase in ovarian granulosa cell carcinomas (p<0.05), an over 3-fold increase in malignant tumors (p<0.02), and a 4.6-fold increase in metastatic incidence. These results are the first to demonstrate an increased susceptibility in vivo of PPAR haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPAR may act as a tumor modifier of skin, ovarian and breast cancers. These data also support evidence suggesting a beneficial role for PPAR specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis., tumor modifier, breast cancer, chemical carcinogenesis, DMBA
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