Journal Article A Rat Model to Study the Effects of Diet-Induced Obesity on Radiation-Induced Mammary Carcinogenesis

Imaoka, Tatsuhiko  ,  Nishimura, Mayumi  ,  Daino, Kazuhiro  ,  Morioka, Takamitsu  ,  Nishimura, Yukiko  ,  Uemura, Hiroji  ,  Akimoto, Kenta  ,  Furukawa, Yuki  ,  Fukushi, Masahiro  ,  Wakabayashi, Keiji  ,  Mutoh, Michihiro  ,  Shimada, Yoshiya

185 ( 5 )  , pp.505 - 515 , 2016-05 , Allen Press, Inc
A detailed understanding of the relationship between radiation-induced breast cancer and obesity is needed for appropriate risk management and prevention of developing a second cancer in cancer survivors who receive radiotherapy. The study reported herein aimed to develop an animal model to study this relationship by combining two existing Sprague-Dawley rat models of radiation-induced mammary carcinogenesis and diet-induced obesity. Female rats that had been fed a high-fat diet for 4 weeks were categorized as obesity prone or obesity resistant based on their body weight at 7 weeks of age, at which time they were irradiated with 4 Gy. Control rats were fed a standard diet and irradiated at the same time and in the same manner. All rats were maintained on their initial diets and assessed for palpable mammary cancers once a week for the following 30 weeks. The obesity-prone rats were heavier than those in the other groups. They were also younger than the other rats at the time when their mammary carcinomas were first detected, and their carcinoma weights were greater. Tendency of higher blood levels of insulin and leptin was observed in the obesity-prone rats than in the other two groups. Blood angiotensin II levels were elevated in the obesity-prone and obesity-resistant rats. Genes related to translation and oxidative phosphorylation were upregulated in the carcinomas of obesity-prone rats. Expression profiles from human breast cancers were used to validate this animal model. As angiotensin is potentially an important factor in obesity-related morbidities and breast cancer, a second set of rats was fed in a similar manner, irradiated, and then treated with an angiotensin-receptor blocker, losartan or candesartan. Neither blocker altered mammary carcinogenesis; analyses of losartan-treated animals indicated that expression of renin in the renal cortex and of Agtr1a (angiotensin II receptor, type 1) in cancer tissue was significantly upregulated, suggesting the presence of compensating mechanisms for blocking angiotensin-receptor signaling. Thus, obesity-related elevation of insulin and leptin blood levels and an increase in available energy may facilitate sustained protein synthesis in cancer cells, which is needed for rapid cancer development.

Number of accesses :  

Other information