β2-microglobulin has a different regulatory molecular mechanism between ER and ER breast cancer with HER2.

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.