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

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma), 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 PPARgamma ligands might promote differentiation and/or regression of mammary tumors. To directly evaluate the role of PPARgamma in mammary carcinogenesis, PPARgamma 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 PPARgamma(+/+) littermate controls, PPARgamma(+/-) 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, PPARgamma(+/-) 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, PPARgamma(+/-) 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 PPARgamma haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPARgamma may act as a tumor modifier of skin, ovarian and breast cancers. The data also support evidence suggesting a beneficial role for PPARgamma-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.

• Authors: Christopher J Nicol, Michung Yoon, Jerrold M Ward, Masamichi Yamashita, Katsumi Fukamachi, Jeffrey M Peters, Frank J Gonzalez
• Journal: Carcinogenesis (Carcinogenesis) Vol. 25 Issue 9 Pg. 1747-55 (Sep 2004) ISSN: 0143-3334 [Print] England
• PMID: 15073042 (Publication Type: Comparative Study, Journal Article)

Chemical References

• DNA Primers
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• 9,10-Dimethyl-1,2-benzanthracene

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Animals
• DNA Primers (chemistry)
• Disease Susceptibility
• Female
• Heterozygote
• Humans
• Mammary Neoplasms, Experimental (chemically induced, pathology)
• Mice
• Ovarian Neoplasms (chemically induced, pathology)
• RNA, Messenger (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin Neoplasms (chemically induced, pathology)
• Survival Rate
• Transcription Factors (genetics, physiology)
• Zinc Fingers