GABRP sustains the stemness of triple-negative breast cancer cells through EGFR signaling. (28th August 2021)

• Record Type: Journal Article
• Authors: Li, Xiyin; Wang, Hairui; Yang, Xing; Wang, Xiaoqi; Zhao, Lina; Zou, Li; Yang, Qin; Hou, Zongliu; Tan, Jing; Zhang, Honglei; Nie, Jianyun; Jiao, Baowei
• Is Part Of: Cancer letters. Volume 514(2021)
• Page Start: 90
• Page End: 102
• Publication Date: 2021-08-28
• Subjects: Stemness -- GABRP -- EGFR -- Gefitinib; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.04.028
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Effective treatment regimens for triple-negative breast cancer (TNBC) are relatively scarce due to a lack of specific therapeutic targets. Epidermal growth factor receptor (EGFR) signaling is highly active in TNBC and is associated with poor prognosis. Most EGFR antagonists, which significantly improve outcome in lung and colon cancer, have shown limited clinical effects in breast cancer. However, limiting EGFR expression in TNBC is a potential strategy for improving the clinical efficacy of EGFR antagonists. Here, we found that the gamma-aminobutyric acid type A receptor π subunit (GABRP), as a membrane protein enriched in TNBC stem cells, interacted with EGFR and significantly sustained its expression, resulting in stemness maintenance and chemotherapy resistance. Silencing GABRP induced down-regulation of EGFR signaling, which hindered cell stemness and enhanced sensitivity to chemotherapies, including paclitaxel, doxorubicin, and cisplatin. We also identified that retigabine, an FDA-approved drug for adjunctive treatment of seizures, increased the sensitivity of EGFR to gefitinib in gefitinib-resistant cells. Our findings show that GABRP can sustain the stemness of TNBC via modulating EGFR expression, suggesting that GABRP may be a potential therapeutic target that can address EGFR inhibitor resistance in TNBC. Highlights: GABRP interacts with EGFR and sustains EGFR expression. GBARP maintains the stemness of BCSCs. GABRP contributes to drug sensitivity through EGFR. Retigabine increases the sensitivity of gefitinib.