PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ.
PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ.
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DOI：
10.1371/journal.pone.0051239
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lee PP
中科院分区：
文献类型：
--
作者：
Yu H;Simons DL;Segall I;Carcamo-Cavazos V;Schwartz EJ;Yan N;Zuckerman NS;Dirbas FM;Johnson DL;Holmes SP;Lee PP
淋巴结转移是乳腺癌发展过程中的一个关键事件。因此，了解促进局部淋巴结转移进展的潜在机制是重要的。我们对来自人乳腺肿瘤和淋巴结转移的纯化肿瘤细胞进行了基因表达谱分析。通过微阵列网络分析，我们发现淋巴结转移性肿瘤细胞中多梳抑制复合物2 （PRC2）核心亚基EED和EZH2的表达高于原发肿瘤细胞，并通过实时PCR验证了这一结果。此外，免疫组织化学（IHC）染色和全组织切片定量图像分析显示，配对乳腺原发肿瘤淋巴结中表达EZH2的肿瘤细胞显著增加，与肿瘤细胞原位增殖密切相关。我们进一步探讨了PRC2基因在转移性肿瘤细胞中的上调机制，通过GSEA分析发现淋巴结转移中E2F基因、MYC靶点上调，肿瘤抑制基因E-cadherin靶点下调。通过免疫组化，我们检测了配对原发/淋巴结样本中EZH2潜在靶点E-cadherin的表达，发现在配对原发肿瘤的淋巴结转移中，E-cadherin的表达显著降低。本研究发现，与原发肿瘤相比，表观遗传沉默复合物PRC2/EED-EZH2在乳腺癌淋巴结转移中过表达，并与肿瘤细胞原位增殖呈正相关。同时，PRC2靶蛋白E-cadherin在淋巴结转移中显著降低，提示PRC2通过抑制E-cadherin促进淋巴结转移过程中的上皮间充质转化（epithelial mesenchymal transition， EMT）。这些结果表明，PRC2蛋白介导的表观遗传调控可能为淋巴结转移性肿瘤细胞的生长提供了额外的优势。这为治疗和预防乳腺癌淋巴结转移开辟了表观遗传药物开发的可能性。
Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression. We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors. This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer.