Vieira Renan Fl, Sanchez Sawyer R, Arumugam Menusha, Mower Peyton D, Curtin Meghan C, Jackson Abigail E, Gallop Molly R, Wright Jillian, Bowles Alexis, Ducker Gregory S, Hilgendorf Keren I, Chaix Amandine
Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA.
Utah Diabetes and Metabolism Research Center, Salt Lake City, UT, USA.
Cancer Metab. 2025 Aug 28;13(1):39. doi: 10.1186/s40170-025-00407-0.
Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.
肥胖是乳腺癌（BC）的既定风险因素，但其背后关联的具体机制仍不明确。脂质代谢失调已成为癌细胞生物学中的关键因素，尽管肥胖常伴有高脂血症，但脂质水平升高对BC生长的单独影响尚未经过实验验证。利用免疫健全小鼠的肥胖加速BC生长的E0771和Py230原位模型，我们研究了全身脂质对肿瘤生长的作用。结合饮食和基因小鼠模型，我们发现即使在没有肥胖或血糖和/或胰岛素水平改变的情况下，循环脂质升高也足以加速BC肿瘤生长。药物降低全身脂质水平可减轻肥胖小鼠的BC生长，表明脂质在促进肿瘤扩张中起直接作用。值得注意的是，我们还表明，仅体重减轻而没有相应降低脂质水平（如生酮饮食诱导的那样）并不能预防BC，这凸显了在肥胖相关BC中靶向脂质代谢的必要性。我们的研究结果确立了高脂血症是BC进展的关键驱动因素，并表明降脂干预可能是降低肥胖个体BC风险的一种有前景的策略。
