Loree Jonathan, Koturbash Igor, Kutanzi Kristy, Baker Mike, Pogribny Igor, Kovalchuk Olga
Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada.
Int J Radiat Biol. 2006 Nov;82(11):805-15. doi: 10.1080/09553000600960027.
Ionizing radiation is a potent mammary gland carcinogen, yet the exact molecular etiology of radiation-induced breast cancer remains unknown.
Our study utilized a rat model of breast carcinogenesis to analyse the molecular and epigenetic changes induced in mammary gland tissue upon exposure to ionizing radiation (IR). Using a methylation-sensitive cytosine extension assay we studied the IR-induced changes in DNA methylation. In parallel, we analysed the expression of proteins involved in DNA methylation, DNA repair and cell proliferation control. Molecular changes were related to cellular proliferation and apoptosis.
We found that IR led to a loss of genomic cytosine methylation in the exposed mammary tissue. Global DNA hypomethylation was paralleled by reduction in the levels of maintenance (DNMT1) and de novo (DNMT3a and 3b) DNA methyltransferases and methyl-binding protein MeCP2. The observed DNA hypomethylation was linked, at least in part, to activation of DNA repair processes. Concurrently, we observed increased levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), phosphorylated AKT kinase (p-AKT), cyclin D1 and proliferating cells nuclear antigen (PCNA) proteins, suggesting IR alters intra-cellular signaling and cell cycle control mechanisms in mammary tissue. We also noted a significant induction of apoptosis in the exposed tissue 6 hours after irradiation. The observed apoptosis levels were paralleled by the slight elevation of cellular proliferation.
We have demonstrated that a single exposure to 5 Gy of X rays leads to noticeable epigenetic changes in the rat mammary gland that occurred in the context of activation of DNA damage repair and alterations in the pro-survival growth-stimulatory cellular signaling pathways. The possible cellular repercussions of the observed changes in relationship to breast carcinogenesis are discussed.
电离辐射是一种强效的乳腺致癌物，但辐射诱发乳腺癌的确切分子病因仍不清楚。
我们的研究利用乳腺癌发生的大鼠模型，分析暴露于电离辐射（IR）后乳腺组织中诱导的分子和表观遗传变化。使用甲基化敏感的胞嘧啶延伸测定法，我们研究了IR诱导的DNA甲基化变化。同时，我们分析了参与DNA甲基化、DNA修复和细胞增殖控制的蛋白质的表达。分子变化与细胞增殖和凋亡相关。
我们发现IR导致暴露的乳腺组织中基因组胞嘧啶甲基化缺失。整体DNA低甲基化与维持性（DNMT1）和从头（DNMT3a和3b）DNA甲基转移酶以及甲基结合蛋白MeCP2水平的降低同时出现。观察到的DNA低甲基化至少部分与DNA修复过程的激活有关。同时，我们观察到磷酸化细胞外信号调节激酶（p-ERK1/2）、磷酸化AKT激酶（p-AKT）、细胞周期蛋白D1和增殖细胞核抗原（PCNA）蛋白水平升高，表明IR改变了乳腺组织中的细胞内信号传导和细胞周期控制机制。我们还注意到照射后6小时暴露组织中凋亡明显增加。观察到的凋亡水平与细胞增殖的轻微升高同时出现。
我们已经证明，单次暴露于5 Gy的X射线会导致大鼠乳腺中明显的表观遗传变化，这些变化发生在DNA损伤修复激活和促生存生长刺激细胞信号通路改变的背景下。讨论了观察到的变化与乳腺癌发生相关的可能细胞影响。
