Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, The First Affiliated Hospital, Shenzhen University Health Science Center, Shenzhen, 518060, China.
Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China.
Cell Death Dis. 2023 Jun 23;14(6):370. doi: 10.1038/s41419-023-05888-9.
Basal-like breast cancers (BLBCs) are among the most aggressive cancers, partly due to their enrichment of cancer stem cells (CSCs). Breast CSCs can be generated from luminal-type cancer cells via epithelial-mesenchymal transition (EMT). GATA3 maintains luminal cell fate, and its expression is lost or reduced in BLBCs. However, deletion of Gata3 in mice or cells results in early lethality or proliferative defects. It is unknown how loss-of-function of GATA3 regulates EMT and CSCs in breast cancer. We report here that haploid loss of Gata3 in mice lacking p18Ink4c, a cell cycle inhibitor, up-regulates Fra1, an AP-1 family protein that promotes mesenchymal traits, and downregulates c-Fos, another AP-1 family protein that maintains epithelial fate, leading to activation of EMT and promotion of mammary tumor initiation and metastasis. Depletion of Gata3 in luminal tumor cells similarly regulates Fra1 and c-Fos in activation of EMT. GATA3 binds to FOSL1 (encoding FRA1) and FOS (encoding c-FOS) loci to repress FOSL1 and activate FOS transcription. Deletion of Fra1 or reconstitution of Gata3, but not reconstitution of c-Fos, in Gata3 deficient tumor cells inhibits EMT, preventing tumorigenesis and/or metastasis. In human breast cancers, GATA3 expression is negatively correlated with FRA1 and positively correlated with c-FOS. Low GATA3 and FOS, but high FOSL1, are characteristics of BLBCs. Together, these data provide the first genetic evidence indicating that loss of function of GATA3 in mammary tumor cells activates FOSL1 to promote mesenchymal traits and CSC function, while concurrently repressing FOS to lose epithelial features. We demonstrate that FRA1 is required for the activation of EMT in GATA3 deficient tumorigenesis and metastasis.
基底样乳腺癌 (BLBC) 是最具侵袭性的癌症之一,部分原因是其富含癌症干细胞 (CSC)。乳腺 CSCs 可通过上皮-间充质转化 (EMT) 从腔型癌细胞中产生。GATA3 维持腔细胞命运,其在 BLBC 中的表达丢失或减少。然而,在小鼠或细胞中敲除 Gata3 会导致早期致死或增殖缺陷。目前尚不清楚 GATA3 的功能丧失如何调节乳腺癌中的 EMT 和 CSCs。我们在此报告,在缺乏细胞周期抑制剂 p18Ink4c 的小鼠中,Gata3 的单倍体缺失上调了 Fra1,一种促进间充质特征的 AP-1 家族蛋白,下调了 c-Fos,另一种维持上皮命运的 AP-1 家族蛋白,导致 EMT 的激活和促进乳腺肿瘤的起始和转移。在腔型肿瘤细胞中耗尽 Gata3 同样调节 Fra1 和 c-Fos 在 EMT 的激活中。GATA3 结合到 FOSL1(编码 Fra1)和 FOS(编码 c-Fos)基因座以抑制 FOSL1 并激活 FOS 转录。在 Gata3 缺陷肿瘤细胞中缺失 Fra1 或重建 Gata3,但不重建 c-Fos,可抑制 EMT,阻止肿瘤发生和/或转移。在人类乳腺癌中,GATA3 表达与 FRA1 呈负相关,与 c-FOS 呈正相关。低 GATA3 和 FOS,但高 FOSL1,是 BLBC 的特征。总之,这些数据提供了第一个遗传证据,表明乳腺肿瘤细胞中 GATA3 的功能丧失激活 FOSL1 以促进间充质特征和 CSC 功能,同时抑制 FOS 以丧失上皮特征。我们证明 Fra1 是 GATA3 缺陷肿瘤发生和转移中 EMT 激活所必需的。
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