Paradoxical Influences of Dietary Obesity in the Early Life on the Mammary Microenvironment Towards Breast Tumorigenesis in Mice

OBJECTIVES: Obesity has been shown complex associations with breast cancer: a clear positive association in post-menopausal women but an undefined negative association in pre-menopausal women. Moreover, early-life exposure plays a critical role in cancer development later in life. This study aimed to investigate how dietary obesity in early life, mimicking human childhood and adolescence, influences the mammary microenvironment towards breast tumorigenesis in mice METHODS: Thirty-two female C57BL/6 mice were fed a low-fat diet (LF, 10% kcal fat) or a high-fat diet (HF, 60% kcal fat) starting at 4 wks of age for 8 wks. Half mice were sacrificed after 8-wk feeding, and the rest were switched to a normal chow diet (LabDiet#5P76) for additional 12 wks. A panel of metabolic parameters, inflammatory cytokines, folate receptors, as well as genes in the tumorigenic Wnt pathway in the mammary tissue were assessed. RESULTS: HF (8-wk feeding) elevated body weight (p < 0.05), and the increase remains significant after switching to the normal chow diet until sacrifice at 24 wks of age. HF reduced expressions of metabolic parameters Pparγ (p = 0.08) and adiponectin (p < 0.05) and the reductions remain after switching to normal chow diet (p < 0.01). Increased expressions of some hormone-related regulators (e.g., aromatase and estrogen receptors) and pro-inflammatory cytokines (e.g., Tnf-α and Il-6) by HF were not observed until switching to the normal chow diet for 12 wks (p < 0.05). HF increased expressions of folate transporter 1 (p = 0.07) and folate receptor1 (Flor1, p < 0.01) and the significance also remains after switching to normal chow diet (p < 0.01). Paradoxical changes of Wnt-signaling target genes (Cyclin D1, C-Myc, Axin 2) and level of active β-catenin was observed: the expressions increased right after 8-wk HF feeding but decreased after switching to normal chow diet for 12 weeks (p < 0.05). CONCLUSIONS: These interesting findings provided an important mechanistic understanding of the apparent paradoxical associations between obesity and breast tumorigenesis: early-life obesity alters mammary metabolic and inflammatory microenvironment in favor of breast tumorigenesis, whereas improves folate status towards preventing breast tumorigenesis in the later life potentially via an epigenetic mechanism. FUNDING SOURCES: This project was supported by USDA/NIFA (Hatch#1,013,548).