Yin Jiali, Tu Gang, Peng Meixi, Zeng Huan, Wan Xueying, Qiao Yina, Qin Yilu, Liu Manran, Luo Haojun
Key Laboratory of Laboratory Medical Diagnostics designated by Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
FASEB J. 2020 Mar;34(3):4557-4572. doi: 10.1096/fj.201901384RR. Epub 2020 Feb 6.
Triple-negative breast cancer (TNBC) is a group of breast cancer with heterogeneity and poor prognosis and effective therapeutic targets are not available currently. TNBC has been recognized as estrogen-independent breast cancer, while the novel estrogen receptor, namely G protein-coupled estrogen receptor (GPER), was claimed to mediate estrogenic actions in TNBC tissues and cell lines. Through mRNA microarrays, lncRNA microarrays, and bioinformatics analysis, we found that GPER is activated by 17β-estradiol (E2) and GPER-specific agonist G1, which downregulates a novel lncRNA (termed as lncRNA-Glu). LncRNA-Glu can inhibit glutamate transport activity and transcriptional activity of its target gene VGLUT2 via specific binding. GPER-mediated reduction of lncRNA-Glu promotes glutamate transport activity and transcriptional activity of VGLUT2. Furthermore, GPER-mediated activation of cAMP-PKA signaling contributes to glutamate secretion. LncRNA-Glu-VGLUT2 signaling synergizes with cAMP-PKA signaling to increase autologous glutamate secretion in TNBC cells, which activates glutamate N-methyl-D-aspartate receptor (NMDAR) and its downstream CaMK and MEK-MAPK pathways, thus enhancing cellular invasion and metastasis in vitro and in vivo. Our data provide new insights into GPER-mediated glutamate secretion and its downstream signaling NMDAR-CaMK/MEK-MAPK during TNBC invasion. The mechanisms we discovered may provide new targets for clinical therapy of TNBC.
三阴性乳腺癌（TNBC）是一类具有异质性且预后较差的乳腺癌，目前尚无有效的治疗靶点。TNBC被认为是雌激素非依赖性乳腺癌，而新型雌激素受体，即G蛋白偶联雌激素受体（GPER），被认为可介导TNBC组织和细胞系中的雌激素作用。通过mRNA微阵列、lncRNA微阵列和生物信息学分析，我们发现GPER可被17β-雌二醇（E2）和GPER特异性激动剂G1激活，这会下调一种新型lncRNA（称为lncRNA-Glu）。lncRNA-Glu可通过特异性结合抑制其靶基因VGLUT2的谷氨酸转运活性和转录活性。GPER介导的lncRNA-Glu减少会促进VGLUT2的谷氨酸转运活性和转录活性。此外，GPER介导的cAMP-PKA信号激活有助于谷氨酸分泌。lncRNA-Glu-VGLUT2信号与cAMP-PKA信号协同作用，增加TNBC细胞中的自体谷氨酸分泌，从而激活谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）及其下游的CaMK和MEK-MAPK途径，进而增强体外和体内的细胞侵袭和转移。我们的数据为TNBC侵袭过程中GPER介导的谷氨酸分泌及其下游信号NMDAR-CaMK/MEK-MAPK提供了新的见解。我们发现的机制可能为TNBC的临床治疗提供新的靶点。
