Elhinnawi Manar A, Okita Yukari, Shigematsu Katsunobu, Abdelaziz Mohammed, Shiratani Rie, Kawanishi Kunio, Hengphasatporn Kowit, Dang Cao Thuy Linh, Shigeta Yasuteru, Kato Mitsuyasu
Department of Experimental Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt.
Cancer Sci. 2025 Feb;116(2):432-443. doi: 10.1111/cas.16419. Epub 2024 Nov 28.
Breast cancer is a heterogeneous disease and is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) is a relatively aggressive subtype of breast cancer, which is difficult to treat. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is overexpressed in various types of cancers, including breast cancer, especially TNBC. In this study, bioinformatic analyses revealed enhanced fibroblast growth factor receptor 1 (FGFR1) signaling in patients with invasive breast cancer, and the GPNMB/FGFR1 group exhibited a lower probability of relapse-free survival (RFS) than the GPNMB/FGFR1 group. Additionally, we observed that GPNMB and FGFR1 were essential for sphere formation, cellular migration, and epithelial-mesenchymal transition (EMT)-like changes in TNBC cells. To explore the mutual interaction between these two molecules, we conducted in silico protein-protein docking studies and molecular dynamics simulations. The results revealed that GPNMB isoform b exhibits high binding affinity for FGFR1 isoform c (FGFR1c), which correlates with cancer aggressiveness. We also confirmed the interaction between GPNMB and FGFR1 in TNBC cells. Furthermore, our study demonstrated that GPNMB is essential for AKT phosphorylation at T308 following FGF2 stimulation, resulting in high affinity for FGFR1c. Inhibition of AKT phosphorylation substantially reduces the tumorigenic potential of TNBC cells.
乳腺癌是一种异质性疾病，也是女性中最常见的癌症之一。三阴性乳腺癌（TNBC）是乳腺癌中一种相对侵袭性较强的亚型，难以治疗。糖蛋白非转移性黑色素瘤蛋白B（GPNMB）是一种I型跨膜蛋白，在包括乳腺癌尤其是TNBC在内的各种癌症中均有过表达。在本研究中，生物信息学分析显示浸润性乳腺癌患者的成纤维细胞生长因子受体1（FGFR1）信号增强，且GPNMB/FGFR1组的无复发生存率（RFS）低于GPNMB/FGFR1组。此外，我们观察到GPNMB和FGFR1对TNBC细胞的球体形成、细胞迁移和上皮-间质转化（EMT）样变化至关重要。为了探究这两种分子之间的相互作用，我们进行了计算机辅助蛋白质-蛋白质对接研究和分子动力学模拟。结果显示，GPNMB同工型b对FGFR1同工型c（FGFR1c）具有高结合亲和力，这与癌症侵袭性相关。我们还证实了TNBC细胞中GPNMB与FGFR1之间的相互作用。此外，我们的研究表明，GPNMB对FGF2刺激后AKT在T308位点的磷酸化至关重要，从而导致对FGFR1c具有高亲和力。抑制AKT磷酸化可显著降低TNBC细胞的致瘤潜力。
