Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Ther. 2018 Dec;17(12):2689-2701. doi: 10.1158/1535-7163.MCT-18-0399. Epub 2018 Sep 20.
Breast cancer stem-like cells (BCSC) are implicated in cancer recurrence and metastasis of triple-negative breast cancer (TNBC). We have recently discovered that ganglioside GD2 expression defines BCSCs and that ST8SIA1 regulates GD2 expression and BCSC function. In this report, we show that ST8SIA1 is highly expressed in primary TNBC; its expression is positively correlated with the expression of several BCSC-associated genes such as BCL11A, FOXC1, CXCR4, PDGFRβ, SOX2, and mutations in p53. CRISPR knockout of ST8SIA1 completely inhibited BCSC functions, including tumorigenesis and mammosphere formation. Mechanistic studies discovered activation of the FAK-AKT-mTOR signaling pathway in GD2 BCSCs, and its tight regulation by ST8SIA1. Finally, knockout of ST8SIA1 completely blocked tumor growth and metastasis by TNBC cells. In summary, these data demonstrate the mechanism by which ST8SIA1 regulates tumor growth and metastasis in TNBC and identifies it as a novel therapeutic target.
乳腺癌干细胞样细胞 (BCSC) 与三阴性乳腺癌 (TNBC) 的癌症复发和转移有关。我们最近发现，神经节苷脂 GD2 的表达定义了 BCSC，而 ST8SIA1 调节 GD2 的表达和 BCSC 功能。在本报告中，我们表明 ST8SIA1 在原发性 TNBC 中高度表达；其表达与几个 BCSC 相关基因的表达呈正相关，如 BCL11A、FOXC1、CXCR4、PDGFRβ、SOX2 和 p53 突变。CRISPR 敲除 ST8SIA1 完全抑制了 BCSC 的功能，包括肿瘤发生和类乳腺球体形成。机制研究发现，GD2 BCSC 中 FAK-AKT-mTOR 信号通路被激活，而 ST8SIA1 对其进行了严格的调节。最后，TNBC 细胞中 ST8SIA1 的敲除完全阻断了肿瘤的生长和转移。总之，这些数据表明 ST8SIA1 调节 TNBC 中肿瘤生长和转移的机制，并将其鉴定为一种新的治疗靶点。
