Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA.
Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, 28903 Madrid, Spain.
Cells. 2022 Aug 17;11(16):2558. doi: 10.3390/cells11162558.
Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a high-fat and high-sugar (HFHS) diet during defined developmental windows determines mammary tumor incidence and latency in carcinogen-treated mice. Mammary tumor incidence is significantly increased in mice receiving a HFHS post-weaning diet (high-tumor mice, ) compared to those receiving a HFHS diet during gestation (low-tumor mice, ). The current study revealed that the mammary stem cell (MaSC) population was significantly increased in mammary glands from HT compared to LT mice. expression was increased in mammary stromal cells from HT mice, where it promoted MaSC self-renewal. The increased expression was induced by DNA hypomethylation of the Pr1 promoter, mediated by a decrease in Dnmt3b levels. Mammary tissues from HT mice also had reduced levels of Igfbp5, leading to increased bioavailability of tissue Igf1. This study provides novel insights into how early dietary exposures program mammary cancer risk, demonstrating that effective dietary intervention can reduce mammary cancer incidence.
饮食是影响乳腺癌风险的一个关键环境因素，最近的证据表明，早期发育过程中的饮食暴露会影响终生的乳腺癌易感性。为了阐明潜在的机制，我们使用了已建立的交叉喂养小鼠模型，其中在特定的发育窗口中暴露于高脂肪和高糖（HFHS）饮食会确定致癌物处理小鼠的乳腺肿瘤发生率和潜伏期。与接受妊娠期 HFHS 饮食（低肿瘤小鼠）的小鼠相比，接受断奶后 HFHS 饮食（高肿瘤小鼠）的小鼠乳腺肿瘤发生率显著增加。本研究表明，与 LT 小鼠相比，HT 小鼠的乳腺干细胞（MaSC）群体显著增加。来自 HT 小鼠的乳腺基质细胞中表达增加，促进了 MaSC 的自我更新。表达增加是由 Pr1 启动子的 DNA 低甲基化引起的，这是由 Dnmt3b 水平降低介导的。HT 小鼠的乳腺组织中还存在 Igfbp5 水平降低，导致组织 Igf1 的生物利用度增加。这项研究为早期饮食暴露如何影响乳腺癌风险提供了新的见解，表明有效的饮食干预可以降低乳腺癌的发病率。
