ABSTRACT

Epidemiological studies have established obesity as a critical risk factor for postmenopausal breast cancer (post-BC), whereas a reverse association holds prior to menopause. A significant scientific gap exists in understanding the mechanism(s) underpinning this epidemiological phenomenon, particularly the reverse association between obesity and premenopausal breast cancer (pre-BC). This study aimed to understand how folate metabolism and DNA methylation inform the association between obesity and pre-BC. Fifty normal breast tissue samples were collected from premenopausal women who underwent reduction mammoplasty. We modified the Lactobacillus Casei microbiological folate assay and measured folate levels in our breast tissue samples. The DNA methylation of LINE-1, a biomarker of genome-wide methylation, and the expression of a panel of breast cancer-related genes was measured by pyrosequencing and real-time PCR. We found that a high BMI is associated with an increase of folate levels in mammary tissue, with an increase of 2.65 ng/g of folate per every 5-unit increase of BMI (p < 0.05). LINE-1 DNA methylation was significantly associated with BMI (p < 0.05), and marginally associated with folate concentration (p = 0.087). A high expression of SFRP1 was observed in subjects with high BMI or high folate status (p < 0.05). This study demonstrated that, in premenopausal women, obesity is associated with increased mammary folate status, genome-wide DNA methylation and SFRP1 gene expression. Our findings indicated that the improved folate and epigenetic status represents a novel mechanism responsible for the reverse association between obesity and pre-BC.

摘要

流行病学研究已将肥胖确定为绝经后乳腺癌 (post-BC) 的关键危险因素，而在绝经前存在相反的关联。在理解支持这种流行病学现象的机制方面存在重大的科学差距，特别是肥胖与绝经前乳腺癌（pre-BC）之间的反向关联。本研究旨在了解叶酸代谢和 DNA 甲基化如何告知肥胖与前 BC 之间的关联。从接受缩小乳房成形术的绝经前妇女收集了 50 个正常乳房组织样本。我们修改了干酪乳杆菌微生物叶酸测定并测量了我们乳房组织样本中的叶酸水平。LINE-1的DNA甲基化，全基因组甲基化的生物标志物，以及通过焦磷酸测序和实时PCR测量一组乳腺癌相关基因的表达。我们发现，高 BMI 与乳腺组织中叶酸水平的增加有关，每增加 5 个单位的 BMI，叶酸增加 2.65 ng/g（p < 0.05）。LINE-1 DNA甲基化与BMI显着相关（p < 0.05），与叶酸浓度相关（p = 0.087）。在高 BMI 或高叶酸状态的受试者中观察到SFRP1的高表达（ p< 0.05)。这项研究表明，在绝经前女性中，肥胖与乳腺叶酸状态、全基因组 DNA 甲基化和SFRP1基因表达增加有关。我们的研究结果表明，改善的叶酸和表观遗传状态代表了一种新的机制，负责肥胖与前 BC 之间的反向关联。