A detailed understanding of the relationship between radiation-induced
breast cancer and
obesity is needed for appropriate risk management and to prevent the development of a secondary
cancer in patients who have been treated with radiation. Our goal was to develop an animal model to study the relationship by combining two existing Sprague-Dawley rat models of radiation-induced mammary
carcinogenesis and diet-induced
obesity. Female rats were fed a high-fat diet for 4 weeks and categorized as
obesity prone or
obesity resistant based on their
body weight at 7 weeks of age, at which time the rats 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 next 30 weeks. The
obesity-prone rats were heavier than those in the other groups. The
obesity-prone rats were also younger than the other animals at the first detection of mammary
carcinomas and their
carcinoma weights were greater. A tendency toward higher
insulin and
leptin blood levels were observed in the
obesity-prone rats compared to 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 and
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 required for rapid
cancer development.