Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cell Stem Cell. 2013 Jul 3;13(1):117-30. doi: 10.1016/j.stem.2013.05.004. Epub 2013 Jun 13.
Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.
早期足月妊娠是预防乳腺癌最有效的自然保护因素之一。为了研究这种效应，我们对来自未生育和已生育、BRCA1 或 BRCA2 基因突变携带者的正常乳腺组织的多种细胞类型的全基因表达和表观遗传谱进行了特征分析。我们发现，在 CD44(+)祖细胞中存在显著差异，其中许多与干细胞相关的基因和途径的水平较低，包括细胞周期调节剂 p27，在没有 BRCA1/BRCA2 突变的已生育女性中。我们还注意到，在已生育女性中，CD44(+)p27(+)细胞的频率显著降低，并通过外植体培养表明，与生育相关的信号通路在调节 p27(+)细胞数量及其增殖方面发挥作用。我们的研究结果表明，控制 p27(+)乳腺上皮细胞及其数量的途径与乳腺癌风险相关，可用于癌症风险评估和预防。
