SGLT1 is required for the survival of triple‐negative breast cancer cells via potentiation of EGFR activity

• Published in: Molecular oncology Vol. 13; no. 9; pp. 1874 - 1886
• Main Authors: Liu, Huiquan, Ertay, Ayse, Peng, Ping, Li, Juanjuan, Liu, Dian, Xiong, Hua, Zou, Yanmei, Qiu, Hong, Hancock, David, Yuan, Xianglin, Huang, Wei‐Chien, Ewing, Rob M., Downward, Julian, Wang, Yihua
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2019; John Wiley and Sons Inc; Wiley
• Subjects: AKT protein; Antibiotics; Breast cancer; Cancer cells; Cancer therapies; Cell Line, Tumor; Cell Survival; Chemotherapy; Colorectal cancer; EGFR; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Ethylenediaminetetraacetic acid; Female; Gene expression; Glucose transport; Homeopathy; Humans; Intracellular; Kinases; Ligands; MAP Kinase Signaling System; Materia medica and therapeutics; Medical prognosis; Medical research; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Prostate cancer; Protein transport; R&D; Research & development; Response rates; Science; SGLT1; Signal transduction; Sodium; Sodium-glucose cotransporter; Sodium-Glucose Transporter 1 - genetics; Sodium-Glucose Transporter 1 - metabolism; Therapeutics; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; triple‐negative breast cancer; Tumors; Xenografts; China; United States > US; triple-negative breast cancer; SGLT1; EGFR
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.12530

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. The epidermal growth factor receptor (EGFR)–sodium/glucose cotransporter 1 (SGLT1) interaction is required for the survival of triple‐negative breast cancer (TNBC) via potentiation of EGFR activity and stabilization of SGLT1 for high uptake of glucose. TCGA analysis reveals a link between SGLT1 status and AKT signalling in TNBC samples. We further demonstrate that SGLT1 positively regulates EGFR activity.