ABSTRACT
BACKGROUND: Our previous study demonstrated that ß2-microglobulin (ß2M) promoted ER+/HER2- breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of ß2M has not been investigated in ER-/HER2+ breast cancer. Here, we aimed to determine the role of ß2M in ER-/HER2+ breast cancer. METHODS: The interaction between ß2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of ß2M 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. ß2M, 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 ß2M in ER-/HER2+ breast cancer cells MDA-MB-453 by co-immunoprecipitation and mass spectrometry. A yeast two-hybrid system and His-pull down experiments verified that ß2M directly interacted with HFE. ß2M 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 ß2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. ß2M 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: ß2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer.
Subject(s)
Apoptosis , Breast Neoplasms , Hemochromatosis Protein , MAP Kinase Signaling System , Receptor, ErbB-2 , beta 2-Microglobulin , Humans , beta 2-Microglobulin/metabolism , beta 2-Microglobulin/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Female , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Cell Line, Tumor , Hemochromatosis Protein/genetics , Hemochromatosis Protein/metabolism , Protein Binding , Gene Expression Regulation, NeoplasticABSTRACT
Temporal attention is voluntarily deployed at specific moments, whereas temporal expectation is deployed according to timing probabilities. When the target appears at an expected moment in a sequence, temporal attention improves performance at the attended moments, but the timing and the precision of the attentional window remain unknown. Here we independently and concurrently manipulated temporal attention-via behavioral relevance-and temporal expectation-via session-wise precision and trial-wise hazard rate-to investigate whether and how these mechanisms interact to improve perception. Our results reveal that temporal attention interacts with temporal expectation-the higher the precision, the stronger the attention benefit, but surprisingly this benefit decreased with delayed onset despite the increasing probability of stimulus appearance. When attention was suboptimally deployed to earlier than expected moments, it could not be reoriented to a later time point. These findings provide evidence that temporal attention and temporal expectation are different mechanisms, and highlight their interplay in optimizing visual performance.