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./nMethods: Depletion of BRCA1 or GATA3 activates p18^INK4C, 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 p18^INK4C, 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./nResults: 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./nConclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.

中文翻译：

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GATA3 在 BRCA1 下游发挥作用，抑制乳腺癌中的 EMT

目的：BRCA1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 可以通过上皮间质转化 (EMT) 程序从癌细胞中产生。我们和其他人之前已经证明 BRCA1 抑制 EMT 并调节多种 EMT 相关转录因子的表达。然而，BRCA1 在 EMT 抑制中发挥作用的下游介质仍然难以捉摸。/n方法： BRCA1 或 GATA3 的耗竭会激活 p18 ^{I NK4C}，这是一种抑制乳腺上皮细胞增殖的细胞周期抑制剂。因此，我们创造了除 p18 ^{I NK4C}缺失外还缺失 Brca1 或 Gata3 的基因工程小鼠，以挽救因 Brca1 或 Gata3 缺陷引起的增殖缺陷。通过使用这些突变小鼠以及人类BRCA1缺陷和丰富的乳腺癌组织和细胞，我们研究并比较了 Brca1 和 Gata3 缺失在乳腺癌 EMT 激活中的作用。/n 结果：我们发现 BRCA1 和 GATA3表达在人类乳腺癌中呈正相关。BRCA1 的缺失会刺激 GATA3 启动子的甲基化，从而抑制 GATA3 转录。我们开发了 Brca1 和 Gata3 缺陷小鼠系统。我们发现小鼠中 Gata3 缺陷会诱导低分化乳腺肿瘤，并激活 EMT，并促进肿瘤的发生和转移。在相同的遗传背景下，Gata3 缺陷型乳腺肿瘤在诱导 EMT 方面与 Brca1 缺陷型肿瘤的表型相似。在 Brca1 缺陷的肿瘤细胞中重建 Gata3 可激活间充质-上皮转化，抑制肿瘤的发生和转移。/n结论：我们的发现首次证明 GATA3 在 BRCA1 下游发挥作用，抑制 EMT，从而控制乳腺肿瘤的发生和转移。