Obesity Accelerates Mouse Mammary Tumor Growth in the Absence of Ovarian Hormones

Abstract

Obesity increases incidence and mortality of breast cancer in postmenopausal women. Mechanisms underlying this association are poorly understood. Suitable animal models are needed to elucidate potential mechanisms for this association. To determine the effects of obesity on mammary tumor growth, nonovariectomized and ovariectomized C57BL/6 mice of various body weights (lean, overweight, and obese) were implanted subcutaneously with mammary tumor cells from syngeneic Wnt-1 transgenic mice. In mice, the lean phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status. Ovariectomy delayed Wnt-1 tumor growth consistent with the known hormone responsiveness of these tumors. However, obesity accelerated tumor growth in ovariectomized but not in nonovariectomized animals. Diet-induced obesity in a syngeneic mouse model of breast cancer enhanced tumor growth, specifically in the absence of ovarian hormones. These results support epidemiological evidence that obesity is associated with increased breast cancer incidence and mortality in postmenopausal but not premenopausal women. In contrast, maintaining a lean body weight phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status.

ACKNOWLEDGMENTS

Animal care was provided in accordance with the procedures outlined in the “Guide for the Care and Use of Laboratory Animals” (NIH Publication No. 86–23, 1985). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This work was supported in part with federal funds from the intramural Center for Cancer Research program and the National Cancer Institute contract N01-CO-12400 to SAIC-Frederick Inc. We would like to acknowledge the expertise and help of Lisa Riffle, Craig Driver, Keith Rogers, and Darlene Green. Grant support is from the Breast Cancer Research Foundation (Stephen D. Hursting) and the Department of Defense (Breast Cancer Research Program Concept Award to Stephen D. Hursting). The publisher or recipient acknowledges the right of the U.S. Government to retain an exclusive, royalty-free license in and to any copyright covering this article.

Notes

^a Abbreviations are as follows: NOVX, nonovariectomized; OVX, ovariectomezed; BMI, body mass index. Comparison of percent body fat in lean, overweight, and obese NOVX and OVX female C57BL/6 mice fed a wide spectrum of calories for 10 wk and premenopausal and postmenopausal women. Body fat was measured by dual energy x-ray absorptiometry in mice and by bioelectrical impedance analysis in premenopausal and postmenopausal women. Percent body fat among the lean, overweight, and obese body weight phenotypes was significantly different in both mice and women (P < 0.05). Values represent the mean ± SD.

^a Abbreviations are as follows: IGF-1, insulin-like growth factor-1; t-PAI, tissue plasminogen activator inhibitor. Serum insulin was measured using a Luminex-based bead method. IGF-1 was measured using a radioimmunoassay kit. Serum adiponectin, resistin and t-PAI concentrations were determined using a Luminex-based bead array assay kit on a LINCOplex simultaneously multianalyte detection system. Mice were on the study for 30 wk (12 mice/group).

∗significantly different than lean mice (P ≤ 0.05);

∗∗ significantly different than overweight mice (P ≤ 0.05).