Ghosh Sagar, Gu Fei, Wang Chou-Miin, Lin Chun-Lin, Liu Joseph, Wang Howard, Ravdin Peter, Hu Yanfen, Huang Tim H M, Li Rong
Department of Molecular Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Breast Cancer Res Treat. 2014 Oct;147(3):653-9. doi: 10.1007/s10549-014-3132-2. Epub 2014 Sep 19.
Early pregnancy in women by the age of 20 is known to have a profound effect on reduction of lifelong breast cancer risk as compared to their nulliparous counterparts. Additional pregnancies further enhance the protection against breast cancer development. Nationwide trend of delayed pregnancy may contribute to the recently reported increase in the incidence of advanced breast cancer among young women in this country. The underlying mechanism for the parity-associated reduction of breast cancer risk is not clearly understood. The purpose of the current study is to use whole-genome DNA methylation profiling to explore a potential association between parity and epigenetic changes in breast tissue from women with early parity and nulliparity. Breast tissue was collected from age-matched cancer-free women with early parity (age < 20; n = 15) or nulliparity (n = 13). The methyl-CpG binding domain-based capture-sequencing technology was used for whole-genome DNA methylation profiling. Potential parity-associated hypermethylated genes were further verified by locus-specific pyrosequencing, using an expanded cohort of parous (n = 19) and nulliparous (n = 16) women that included the initial samples used in the global analysis. Our study identified six genes that are hypermethylated in the parous group (P < 0.05). Pyrosequencing confirmed parity-associated hypermethylation at multiple CpG islands of the FOXA1 gene, which encodes a pioneer factor that facilitates chromatin binding of estrogen receptor α. Our work identifies several potential methylation biomarkers for parity-associated breast cancer risk assessment. In addition, the results are consistent with the notion that parity-associated epigenetic silencing of FOXA1 contributes to long-term attenuation of the estrogenic impact on breast cancer development.
众所周知，与未生育的女性相比，20岁之前怀孕的女性在降低终生患乳腺癌风险方面具有深远影响。额外的怀孕会进一步增强预防乳腺癌发生的保护作用。全国范围内怀孕延迟的趋势可能是导致该国近期报道的年轻女性晚期乳腺癌发病率上升的原因。目前尚不清楚生育相关的乳腺癌风险降低的潜在机制。本研究的目的是利用全基因组DNA甲基化谱来探索早期生育和未生育女性乳腺组织中生育与表观遗传变化之间的潜在关联。从年龄匹配的未患癌症的早期生育（年龄<20岁；n = 15）或未生育（n = 13）的女性中收集乳腺组织。基于甲基化CpG结合域的捕获测序技术用于全基因组DNA甲基化谱分析。通过位点特异性焦磷酸测序进一步验证潜在的生育相关高甲基化基因，使用了一个扩大的生育（n = 19）和未生育（n = 16）女性队列，其中包括全球分析中使用的初始样本。我们的研究确定了在生育组中高甲基化的六个基因（P < 0.05）。焦磷酸测序证实了FOXA1基因多个CpG岛处与生育相关的高甲基化，该基因编码一种先驱因子，可促进雌激素受体α与染色质的结合。我们的工作确定了几种潜在的甲基化生物标志物，用于生育相关的乳腺癌风险评估。此外，结果与以下观点一致，即生育相关的FOXA1表观遗传沉默有助于长期减弱雌激素对乳腺癌发生的影响。
