Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.
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 with DR rats (P < 0.001 for all analyses), and displayed a higher proportion of hormone receptor negative tumors compared with DR rats [OR = 1.78; 95% confidence interval (CI), 0.83-3.81]. Circulating levels of several breast cancer-risk factors, including leptin, adiponectin:leptin ratio, insulin, insulin-like growth factor (IGF)-1, IGF-1:IGF-1 binding protein-3 ratio, and calculated insulin resistance (HOMA-IR) were negatively impacted in DS rats (P < 0.05 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.
111 Shepardson Building, 1173 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1173. henry.thompson@colostate.edu.
Shawna B
SB
Matthews
Zongjian
Z
Zhu
Weiqin
W
Jiang
John N
JN
McGinley
Elizabeth S
ES
Neil
Henry J
HJ
Thompson
D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000473:pathology; D002273:Carcinogens; D004032:Diet; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008770:Methylnitrosourea; D009765:Obesity / Q000150:complications / Q000473:pathology; D017697:Premenopause; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000502:physiology*
D002273:Carcinogens; D008770:Methylnitrosourea