Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Department of Physiology, Vrije Universiteit Medical Center, 1081 HV Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1033-1038. doi: 10.1073/pnas.1525387114. Epub 2017 Jan 17.
Breast tumors contain tumorigenic cancer cells, termed "tumor-initiating cells" (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells.
乳腺肿瘤中含有肿瘤发生细胞，称为“肿瘤起始细胞”（TICs），它们既能自我更新，又能产生非肿瘤发生的乳腺癌细胞（非-TICs）。然而，乳腺肿瘤起始的分子机制仍知之甚少。在这里，我们描述了一种化学筛选策略，以鉴定能增强富含 TIC 的乳腺癌细胞对化疗药物作用的小分子。我们鉴定了与先导化合物 C108 相互作用的蛋白质，包括应激颗粒相关蛋白、GTPase 激活蛋白（SH3 结构域）结合蛋白 2（G3BP2）。G3BP2 通过稳定 Squamous cell carcinoma antigen recognized by T cells 3（SART3）mRNA 来调节乳腺肿瘤起始，从而导致多能转录因子 Octamer-binding protein 4（Oct-4）和 Nanog Homeobox（Nanog）的表达增加。我们的研究结果表明，G3BP2 对乳腺癌起始过程很重要。此外，这些数据表明应激颗粒形成与乳腺癌细胞中肿瘤起始之间可能存在联系。
