GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer.
GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer.
复制标题
GATA3在BRCA1下游功能抑制EMT在乳腺癌中。
作者：
Bai F;Zhang LH;Liu X;Wang C;Zheng C;Sun J;Li M;Zhu WG;Pei XH
目的：BRCA 1的功能丧失与富含癌症干细胞（CSC）的低分化和转移性乳腺癌相关。CSC可以通过上皮-间充质转化（EMT）程序从癌细胞产生。我们和其他人先前已经证明BRCA 1抑制EMT并调节多种EMT相关转录因子的表达。然而，BRCA 1在EMT抑制中的下游介质仍然难以捉摸。方法：BRCA 1或GATA 3的缺失激活p18 INK 4C，一种抑制乳腺上皮细胞增殖的细胞周期抑制剂。因此，我们已经创建了基因工程小鼠与Brca 1或Gata 3损失除了删除p18 INK 4C，以挽救由Brca 1或Gata 3缺陷引起的增殖缺陷。通过使用这些突变小鼠沿着人类BRCA 1缺陷以及熟练的乳腺癌组织和细胞，我们研究和比较了Brca 1和Gata 3缺失在乳腺癌EMT激活中的作用。结果：乳腺癌组织中BRCA 1和GATA 3的表达呈正相关。BRCA 1的缺失刺激GATA 3启动子的甲基化，从而抑制GATA 3的转录。我们建立了Brca 1和Gata 3缺陷小鼠系统。我们发现，Gata 3缺陷诱导小鼠低分化乳腺肿瘤，EMT激活，并促进肿瘤的启动和转移的潜力。Gata 3缺陷型乳腺肿瘤与Brca 1缺陷型乳腺肿瘤在相同遗传背景下诱导EMT的表型相似。Gata 3在Brca 1缺陷肿瘤细胞中的重建激活间质-上皮转化，抑制肿瘤的发生和转移。结论：我们的发现首次证明GATA 3在BRCA 1下游发挥作用，抑制EMT，控制乳腺肿瘤的发生和转移。
Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18INK4C, a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18INK4C, to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.