Nicol Christopher J, Yoon Michung, Ward Jerrold M, Yamashita Masamichi, Fukamachi Katsumi, Peters Jeffrey M, Gonzalez Frank J
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Carcinogenesis. 2004 Sep;25(9):1747-55. doi: 10.1093/carcin/bgh160. Epub 2004 Apr 8.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）是核受体超家族的成员之一，在脂肪细胞分化、II型糖尿病、巨噬细胞对炎症的反应中发挥作用，并且被认为会影响致癌物诱导的结肠癌。体外和体内研究还表明，PPARγ配体可能促进乳腺肿瘤的分化和/或消退。为了直接评估PPARγ在乳腺癌发生中的作用，对PPARγ野生型（+/+）或杂合子（+/-）小鼠每周一次经口灌胃给予1 mg 7,12-二甲基苯并[a]蒽（DMBA），持续6周，总共观察25周。与同基因PPARγ（+/+）同窝对照相比，基于皮肤乳头状瘤小鼠百分比增加1.6倍以及每只小鼠皮肤乳头状瘤数量增加1.7倍（P < 0.05），PPARγ（+/-）小鼠有早期证据表明对DMBA介导的致癌作用易感性增加。同样，PPARγ（+/-）小鼠的存活率也降低了1.5倍（P = 0.059），每只小鼠的总肿瘤发生率增加了1.7倍（P < 0.01）。此外，PPARγ（+/-）小鼠的乳腺腺癌增加了近3倍（P < 0.05），卵巢颗粒细胞癌增加了3倍以上（P < 0.05），恶性肿瘤增加了3倍以上（P < 0.02），转移发生率增加了4.6倍。这些结果首次证明了PPARγ单倍体不足在体内对DMBA介导的致癌作用易感性增加，并表明PPARγ可能作为皮肤、卵巢和乳腺癌的肿瘤调节因子。数据还支持了PPARγ特异性配体在乳腺、卵巢和皮肤癌化学预防中具有有益作用的证据。
