GPNMB is a novel binding partner of FGFR1 that affects tumorigenic potential through AKT phosphorylation in TNBC

Manar A Elhinnawi; Yukari Okita; Katsunobu Shigematsu; Mohammed Abdelaziz; Rie Shiratani; Kunio Kawanishi; Kowit Hengphasatporn; Thuy Linh Dang Cao; Yasuteru Shigeta; Mitsuyasu Kato

doi:10.1111/cas.16419

GPNMB is a novel binding partner of FGFR1 that affects tumorigenic potential through AKT phosphorylation in TNBC

Cancer Sci. 2024 Nov 28. doi: 10.1111/cas.16419. Online ahead of print.

Authors

Manar A Elhinnawi^{1

2

3}, Yukari Okita^{1

4}, Katsunobu Shigematsu¹, Mohammed Abdelaziz^{1

5}, Rie Shiratani¹, Kunio Kawanishi^{1

6}, Kowit Hengphasatporn⁷, Thuy Linh Dang Cao¹, Yasuteru Shigeta⁷, Mitsuyasu Kato^{1

4}

Affiliations

¹ Department of Experimental Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
² Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt.
³ Stem Cells Lab Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt.
⁴ Division of Cell Dynamics, Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan.
⁵ Department of Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt.
⁶ Department of Anatomy, School of Medicine, Showa University, Tokyo, Japan.
⁷ Center for Computational Sciences, University of Tsukuba, Ibaraki, Japan.

PMID: 39609108
DOI: 10.1111/cas.16419

Abstract

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^high/FGFR1^high group exhibited a lower probability of relapse-free survival (RFS) than the GPNMB^low/FGFR1^low 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.

Keywords: cell migration; epithelial–mesenchymal transition; fibroblast growth factor receptor 1; glycoprotein nonmetastatic melanoma protein B; triple‐negative breast cancer.

Abstract

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