2-microglobulin induced apoptosis of tumor cells via the ERK signaling pathway by directly interacting with HFE in HER2-overexpressing breast cancer

• Published in: BMC cancer 2024-08, Vol.24 (1)
• Main Authors: Li, Kesheng, Chai, Dandan, Ren, Shiyang, Lian, Xiaowen, Shi, Xiaoling, Xu, Yang, Bao, Lie, Yang, Suisheng, Liang, Yurong, Li, Xiaoqin, Du, Huifen
• Format: Article
• Language: English
• Subjects: Analysis; Apoptosis; Breast cancer; Care and treatment; Development and progression; Diagnosis; Health aspects; Immunohistochemistry; Mass spectrometry; Metastasis; Protein-protein interactions
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-024-12757-x

Background Our previous study demonstrated that [beta]2-microglobulin ([beta]2M) promoted ER.sup.+/HER2.sup.- breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of [beta]2M has not been investigated in ER.sup.-/HER2.sup.+ breast cancer. Here, we aimed to determine the role of [beta]2M in ER.sup.-/HER2.sup.+ breast cancer. Methods The interaction between [beta]2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of [beta]2M or HFE were performed in MDA-MB-453 cells, and ERK signaling pathway was subsequently analyzed via western blotting. Apoptotic cells were detected using flow cytometer. [beta]2M, HFE, and p-ERK1/2 were examined in tumor and paired adjacent tissues via immunohistochemistry. Results HFE was found to be an interacting protein of [beta]2M in ER.sup.-/HER2.sup.+ breast cancer cells MDA-MB-453 by co-immunoprecipitation and mass spectrometry. A yeast two-hybrid system and His-pull down experiments verified that [beta]2M directly interacted with HFE. [beta]2M and HFE as a complex were mainly located in the cytoplasm, with some on the cytomembrane of MDA-MB-453 cells. In addition to breast cancer cells BT474, endogenous [beta]2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. [beta]2M activated the ERK signaling pathway by interacting with HFE and induced apoptosis of MDA-MB-453 cells. The expression of HFE and p-ERK1/2 showed significantly high levels in HER2-overexpressing breast cancer tumor tissue compared with adjacent normal tissue, consistent with the results obtained from the cell experiments. Conclusions [beta]2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer. Keywords: [beta]2M, Protein-protein interaction, Apoptosis, ERK signaling pathway, HER2-overexpressing breast cancer