Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea

To address the possible involvement of hyperinsulinemia in breast cancer de velopment, we have examined the susceptibility of lean and obese Zucker rat s to N-methyl-N-nitrosourea (MNU)-induced mammary cancer. Fifty-day-old fem ale lean or obese Zucker rats received intraperitoneal (i.p.) injections of 37.5 or 20 mg/kg MNU, respectively. We showed in separate experiments that these doses produce similar levels of DNA methylation in the mammary epith elial cells of the lean and obese animals. Over the course of 29 weeks foll owing MNU treatment, half of the lean rats developed carcinomas of the mamm ary gland, demonstrating that they are of intermediate susceptibility to ma mmary tumorigenesis. During this period, the obese rats developed hyperinsu linemia and insulin resistance as expected. Although palpable tumors develo ped at a similar rate in the lean and obese rats, only 10% of the obese ani mals developed mammary carcinomas. The obese rats, however, developed a hig h incidence (63.3%) of epidermal cysts that occurred mainly in the region o f the mammary glands. A 13.3% incidence of colon carcinomas was also found in the obese rats. These results suggest that the development of hyperinsul inemia does not render the obese Zucker rats more susceptible to mammary gl and carcinogenesis. Our observation of colon carcinomas in obese, but not l ean rats, however, is consistent with evidence that hyperinsulinemia promot es colon cancer in rodents and humans. (C) 2001 Elsevier Science ireland Lt d. All rights reserved.