Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties.
Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties.
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DOI：
10.1186/bcr3588
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发表时间：
2013-12-19
期刊：
影响因子：
--
通讯作者：
Ditzel HJ
中科院分区：
文献类型：
--
作者：
Lin X;Li J;Yin G;Zhao Q;Elias D;Lykkesfeldt AE;Stenvang J;Brünner N;Wang J;Yang H;Bolund L;Ditzel HJ
他莫昔芬耐药性的发展是乳腺癌治疗中一个重要的临床问题。它莫昔芬耐药可能是乳腺癌细胞内获得表观遗传调控的结果，如DNA甲基化，导致雌激素依赖性生长关键基因mRNA表达改变。另外，他莫昔芬耐药可能是由于预先存在的耐药细胞的选择，或两种机制的结合。为了评估这些可能的他莫昔芬耐药机制的贡献，我们应用修饰的DNA甲基化特异性数字核型（MMSDK）和数字基因表达（DGE）结合大量平行测序来分析一个已建立的他莫昔芬耐药细胞系模型（TAMR），该模型由4个耐药细胞系和1个亲本细胞系组成。另一个他莫昔芬耐药细胞系模型系统（LCC1/LCC2）用于验证DNA甲基化和基因表达结果。亲代TAMR敏感细胞系与4个TAMR耐药亚系之间的基因表达和DNA甲基化谱存在显著差异。4个TAMR细胞系表现出较高的甲基化水平，并且在启动子区域基因表达与DNA甲基化呈反比关系。一组基因，包括NRIP1、HECA和FIS1，在耐药细胞系和亲本细胞系中表现出较低的基因表达，同时在耐药细胞系和亲本细胞系中表现出增加的启动子CGI甲基化。在TAMR模型中观察到的甲基化、基因表达和通路改变的大部分也存在于LCC1/LCC2细胞系模型中。更重要的是，在TAMR中，SOX2的高表达以及其他SOX和E2F基因家族成员以及rb相关口袋蛋白基因的改变，突出了干细胞相关通路在耐药细胞中处于中心地位，这意味着在该模型中，癌症启动细胞/癌症干细胞样细胞可能参与了他莫昔芬耐药。我们的数据强调了耐药细胞来自癌症起始细胞/癌症干细胞样细胞的可能性，并暗示这些细胞可能通过表观遗传机制在生长中获得进一步的优势。阐明推定的癌症起始细胞/癌症干细胞的表达和DNA甲基化特征可能为克服他莫昔芬耐药性提供新的策略。
Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal for estrogen-dependent growth. Alternatively, tamoxifen resistance may be due to selection of pre-existing resistant cells, or a combination of the two mechanisms. To evaluate the contribution of these possible tamoxifen resistance mechanisms, we applied modified DNA methylation-specific digital karyotyping (MMSDK) and digital gene expression (DGE) in combination with massive parallel sequencing to analyze a well-established tamoxifen-resistant cell line model (TAMR), consisting of 4 resistant and one parental cell line. Another tamoxifen-resistant cell line model system (LCC1/LCC2) was used to validate the DNA methylation and gene expression results. Significant differences were observed in global gene expression and DNA methylation profiles between the parental tamoxifen-sensitive cell line and the 4 tamoxifen-resistant TAMR sublines. The 4 TAMR cell lines exhibited higher methylation levels as well as an inverse relationship between gene expression and DNA methylation in the promoter regions. A panel of genes, including NRIP1, HECA and FIS1, exhibited lower gene expression in resistant vs. parental cells and concurrent increased promoter CGI methylation in resistant vs. parental cell lines. A major part of the methylation, gene expression, and pathway alterations observed in the TAMR model were also present in the LCC1/LCC2 cell line model. More importantly, high expression of SOX2 and alterations of other SOX and E2F gene family members, as well as RB-related pocket protein genes in TAMR highlighted stem cell-associated pathways as being central in the resistant cells and imply that cancer-initiating cells/cancer stem-like cells may be involved in tamoxifen resistance in this model. Our data highlight the likelihood that resistant cells emerge from cancer-initiating cells/cancer stem-like cells and imply that these cells may gain further advantage in growth via epigenetic mechanisms. Illuminating the expression and DNA methylation features of putative cancer-initiating cells/cancer stem cells may suggest novel strategies to overcome tamoxifen resistance.
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影响因子：
3.7
作者：
Alles MC;Gardiner-Garden M;Nott DJ;Wang Y;Foekens JA;Sutherland RL;Musgrove EA;Ormandy CJ
通讯作者：
Ormandy CJ
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
45.3
作者：
CLARK, GM;OSBORNE, CK;MCGUIRE, WL
通讯作者：
MCGUIRE, WL
影响因子：
3.7
作者：
Dowejko, Albert;Bauer, Richard;Reichert, Torsten E.
通讯作者：
Reichert, Torsten E.
影响因子：
168.9
作者：
Davies, C.;Godwin, J.;Gray, R.;Clarke, M.;Darby, S.;McGale, P.;Wang, Y. C.;Peto, R.;Pan, H. C.;Cutter, D.;Taylor, C.;Ingle, J.
通讯作者：
Ingle, J.