Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, UK.
Mol Oncol. 2019 Sep;13(9):1874-1886. doi: 10.1002/1878-0261.12530. Epub 2019 Jun 14.
Sodium/glucose cotransporter 1 (SGLT1), an essential active glucose transport protein that helps maintain high intracellular glucose levels, was previously shown to interact with epidermal growth factor receptor (EGFR); the SGLT1-EGFR interaction maintains intracellular glucose levels to promote survival of cancer cells. Here, we explore the role of SGLT1 in triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer. We performed TCGA analysis coupled to in vitro experiments in TNBC cell lines as well as in vivo xenografts established in the mammary fat pad of female nude mice. Tissue microarrays of TNBC patients with information of clinical-pathological parameters were also used to investigate the expression and function of SGLT1 in TNBC. We show that high levels of SGLT1 are associated with greater tumour size in TNBC. Knockdown of SGLT1 compromises cell growth in vitro and in vivo. We further demonstrate that SGLT1 depletion results in decreased levels of phospho-EGFR, and as a result, the activity of downstream signalling pathways (such as AKT and ERK) is inhibited. Hence, targeting SGLT1 itself or the EGFR-SGLT1 interaction may provide novel therapeutics against TNBC.
钠/葡萄糖共转运蛋白 1（SGLT1）是一种重要的主动葡萄糖转运蛋白，有助于维持细胞内高葡萄糖水平，先前已显示与表皮生长因子受体（EGFR）相互作用；SGLT1-EGFR 相互作用维持细胞内葡萄糖水平，促进癌细胞存活。在这里，我们探讨了 SGLT1 在三阴性乳腺癌（TNBC）中的作用，TNBC 是最具侵袭性的乳腺癌类型。我们进行了 TCGA 分析，并在 TNBC 细胞系以及雌性裸鼠乳腺脂肪垫中建立的体内异种移植物中进行了体外实验。我们还使用了包含 TNBC 患者临床病理参数信息的组织微阵列来研究 SGLT1 在 TNBC 中的表达和功能。我们表明，SGLT1 水平高与 TNBC 中的肿瘤体积更大相关。SGLT1 的敲低会损害体外和体内的细胞生长。我们进一步证明，SGLT1 耗竭会导致磷酸化 EGFR 水平降低，从而抑制下游信号通路（如 AKT 和 ERK）的活性。因此，针对 SGLT1 本身或 EGFR-SGLT1 相互作用可能为 TNBC 提供新的治疗方法。
