Journal Article

PPARγ influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis

Christopher J. Nicol, Michung Yoon, Jerrold M. Ward, Masamichi Yamashita, Katsumi Fukamachi, Jeffrey M. Peters and Frank J. Gonzalez

in Carcinogenesis

Volume 25, issue 9, pages 1747-1755
Published in print September 2004 | ISSN: 0143-3334
Published online September 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh160
PPARγ influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis

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Peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ ligands might promote differentiation and/or regression of mammary tumors. To directly evaluate the role of PPARγ in mammary carcinogenesis, PPARγ wild-type (+/+) or heterozygous (+/−) mice were administered 1 mg 7,12-dimethylbenz[a]anthracene (DMBA) by gavage once a week for 6 weeks and followed for a total of 25 weeks. Compared with congenic PPARγ(+/+) littermate controls, PPARγ(+/−) 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, PPARγ(+/−) 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, PPARγ(+/−) 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 PPARγ haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPARγ may act as a tumor modifier of skin, ovarian and breast cancers. The data also support evidence suggesting a beneficial role for PPARγ-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.

Keywords: MMTV-LTR, mouse mammary tumor virus long terminal repeat; PPARγ, peroxisome proliferator activated receptor γ.

Journal Article.  7268 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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