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Background: Our previous study demonstrated that β2-microglobulin (β2M) promoted ER+/HER2– breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of β2M has not been investigated in ER–/HER2+ breast cancer. Here, we aimed to determine the role of β2M in ER–/HER2+ breast cancer. Methods: The interaction between β2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of β2M 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. β2M, 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 β2M 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 β2M directly interacted with HFE. β2M 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 β2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. β2M 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: β2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that β2-microglobulin (β2M) promotes the growth and survival of a variety of cancer cells and has different regulatory effects on the expression of Bcl-2 and HER2 in HER2- breast cancer cells. However, β2M-mediated signaling in ER+ and ER- breast cancer with HER2- remains unclear.Methods: β2M expression vector and siRNA were transfected into two types of HER2- breast cancer cells, and the possible relevant signaling molecules were subsequently analyzed by real-time PCR and western blotting. These signaling molecules were also analyzed by real-time PCR and immunohistochemistry (IHC) in two types of HER2- breast cancer tissues, and the associations between β2M and these signaling molecules were assessed using Spearman's correlation analysis.Results: β2M silencing downregulated p-SGK1/SGK1 levels and Bcl-2 expression, and β2M overexpression downregulated p-CREB/CREB and significantly upregulated p-SGK1/SGK1 levels and Bcl-2 expression, and both resulting processes did not affect HER2, HIF-1α, VEGF, and ERK signaling in ER+ breast cancer cells with HER2-. β2M silencing upregulated p-CREB/CREB and VEGF protein and significantly downregulated p-ERK/ERK levels, and β2M overexpression downregulated p-CREB/CREB and VEGF, significantly upregulated p-ERK/ERK levels, and both resulting processes did not affect HIF-1α and SGK1 signaling in ER- breast cancer cells with HER2-. β2M expression was positively correlated with p-CREB, p-SGK1, and Bcl-2 expression and had no correlation with HIF-1α, VEGF, and p-ERK1/2, whereas p-SGK1 exhibited a significantly positive correlation with Bcl-2 expression in cancer tissues of patients with luminal A breast cancer, which coincide with the results obtained from the same molecular types of breast cancer cells except CREB signaling. However, β2M expression did not show a significant correlation with HIF-1α, p-CREB, VEGF, p-SGK1, p-ERK1/2, and Bcl-2 expression in cancer tissues of patients with basal-like breast cancer, which was discordant with the results obtained from the same molecular types of breast cancer cells.Conclusions: β2M has a different molecular regulatory mechanism between ER+ and ER- breast cancer with HER2-, and it may promote tumor survival through the SGK1/Bcl-2 signaling pathway in ER+ breast cancer with HER2- and has no regulatory effects on ER- breast cancer with HER2-. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that β2-microglobulin (β2M) promotes the growth and survival of a variety of cancer cells and has different regulatory effects on the expression of Bcl-2 and HER2 in HER2- breast cancer cells. However, β2M-mediated signaling in ER+ and ER- breast cancer with HER2- remains unclear.Methods: β2M expression vector and siRNA were transfected into two types of HER2- breast cancer cells, and the possible relevant signaling molecules were subsequently analyzed by real-time PCR and western blotting. These signaling molecules were also analyzed by real-time PCR and immunohistochemistry (IHC) in two types of HER2- breast cancer tissues, and the associations between β2M and these signaling molecules were assessed using Spearman's correlation analysis.Results: β2M silencing downregulated p-SGK1/SGK1 levels and Bcl-2 expression, and β2M overexpression downregulated p-CREB/CREB and significantly upregulated p-SGK1/SGK1 levels and Bcl-2 expression, and both resulting processes did not affect HER2, HIF-1α, VEGF, and ERK signaling in ER+ breast cancer cells with HER2-. β2M silencing upregulated p-CREB/CREB and VEGF protein and significantly downregulated p-ERK/ERK levels, and β2M overexpression downregulated p-CREB/CREB and VEGF, significantly upregulated p-ERK/ERK levels, and both resulting processes did not affect HIF-1α and SGK1 signaling in ER- breast cancer cells with HER2-. β2M expression was positively correlated with p-CREB, p-SGK1, and Bcl-2 expression and had no correlation with HIF-1α, VEGF, and p-ERK1/2, whereas p-SGK1 exhibited a significantly positive correlation with Bcl-2 expression in cancer tissues of patients with luminal A breast cancer, which coincide with the results obtained from the same molecular types of breast cancer cells except CREB signaling. However, β2M expression did not show a significant correlation with HIF-1α, p-CREB, VEGF, p-SGK1, p-ERK1/2, and Bcl-2 expression in cancer tissues of patients with basal-like breast cancer, which was discordant with the results obtained from the same molecular types of breast cancer cells.Conclusions: β2M has a different molecular regulatory mechanism between ER+ and ER- breast cancer with HER2-, and it may promote tumor survival through the SGK1/Bcl-2 signaling pathway in ER+ breast cancer with HER2- and has no regulatory effects on ER- breast cancer with HER2-. [ABSTRACT FROM AUTHOR]