Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer

Abstract

In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ≥1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR, 1.59) or obese (HR, 1.70). To investigate this clinical observation in a preclinical setting, ovary-intact female rats were intraperitoneally injected with 50 mg/kg 1-methyl-1-nitrosourea at 21 days of age to simulate premenopausal women with increased risk. Two commercially available strains of Sprague Dawley rat (Taconic Farms) were used which are dietary resistant (DR) or dietary susceptible (DS) to excess weight gain when fed a purified diet containing 32% kcal from fat, similar to levels consumed by the typical American woman. DS rats were approximately 15.5% heavier than DR rats at study termination and plasma leptin indicated a marked difference in adiposity. DS rats had higher incidence (26% increase), multiplicity (2.5-fold increase), and burden (5.4-fold increase) of mammary carcinomas with a concomitant reduction in cancer latency (16% earlier detection) compared to DR rats (P <.001 for all analyses), and displayed a higher proportion of hormone receptor negative tumors compared to DR rats (OR=1.78, 95% CI 0.83-3.81). Circulating levels of several breast cancer risk factors including leptin, adiponectin:leptin ratio, insulin, IGF-1, IGF-1:IGFBP3 ratio, and calculated insulin resistance (HOMA-IR) were negatively impacted in DS rats (P <.05 for all analyses). These findings support further investigation of the effects of excess weight in high-risk premenopausal women and demonstrate a useful preclinical model for rapid evaluation of mechanistic hypotheses.