Pubertal Exposure to High Fat Diet Causes Mouse Strain-dependent Alterations in Mammary Gland Development and Estrogen Responsiveness

OBJECTIVE: Increased adolescent obesity rates in the United States are a significant public health concern. Obesity or increased adiposity during puberty in girls, an important period of breast development and a window of exposure sensitivity, may influence breast development and cancer risk. The purpose of this study was to investigate the impact of a high fat diet on mammary gland development in obesity-susceptible C57BL/6 and obesity-resistant BALB/c mice. DESIGN: Pubertal or adult C57BL/6 and BALB/c mice were fed a high fat diet (HFD) or control diet (CD) from 3 to 7 weeks of age or from 10 to 14 wks of age, respectively. The effects of HFD diet on body weight, adiposity, mammary gland development, and mammary gland response to estrogen were evaluated. RESULTS: Pubertal C57BL/6 mice fed the HFD had a significant increase in body weight and adiposity, and this was accompanied by stunted mammary duct elongation and reduced mammary epithelial cell proliferation. Ovariectomy and estrogen (E) treatment of pubertal HFD-fed C57BL/6 mice showed decreased mammary gland stimulation by E. Amphiregulin, a downstream mediator of pubertal E action, was reduced in mammary glands of HFD-fed C57BL/6 mice. Weight loss and reduced adiposity initiated by switching C57BL/6 mice from HFD to CD restored ductal elongation. Pubertal BALB/c mice fed the HFD did not exhibit a significant increase in body weight or adiposity; HFD caused increased mammary epithelial cell proliferation and had no effect on response to E. HFD had no effect on body weight or the mammary glands of adult mice. CONCLUSIONS: HFD during puberty had a profound strain-specific effect on murine mammary gland development. Obesity and increased adiposity were associated with reduced responsiveness to estrogen and stunted ductal growth. Importantly, the effect of diet and adiposity on the mammary gland was specific to the pubertal period of development.