Effect of Selinexor on epithelial mesenchymal transition pathway in M1/M2 macrophage and breast cancer co-culture model

This study was conducted to investigate the effects of tumor-associated macrophages (TAMs), one of the main components of the tumor microenvironment (TME), on the epithelial–mesenchymal transition (EMT) process in MDA-MB-231 cells and to evaluate the regulatory role of the XPO1 inhibitor Selinexor in this process. Macrophages within the TME can exhibit distinct phenotypes, displaying either proinflammatory (M1) or anti-inflammatory (M2) properties. M1 macrophages play antitumor, proinflammatory, and immune-supportive roles, whereas M2 macrophages are known to be associated with poor prognosis by enhancing tumor cell proliferation, angiogenesis, invasion, and metastatic capacity. The nuclear transport protein XPO1 is responsible for exporting tumor suppressor proteins from the nucleus to the cytoplasm. Overexpression of XPO1 leads to the translocation of these proteins out of the nucleus, resulting in loss of function and inhibition of apoptosis. Selinexor selectively inhibits XPO1, ensuring the nuclear retention of tumor suppressor proteins and thereby reducing cell proliferation and metastatic potential. In this study, a co-culture model was established using MDA-MB-231 cells and Raw 264.7 macrophages polarized into M1 and M2 phenotypes. The effects of Selinexor on EMT markers were evaluated by ICC analysis. The findings demonstrated a significant increase in E-cadherin expression and a decrease in vimentin and N-cadherin expression in the presence of M1 macrophages. In contrast, co-culture with M2 macrophages resulted in increased vimentin and N-cadherin expression and decreased E-cadherin expression. Selinexor treatment was found to reverse these alterations. Overall, the results indicate that Selinexor suppresses EMT and metastatic potential in MDA cells by targeting the TME, suggesting that XPO1 inhibition may represent a promising therapeutic strategy for reducing metastasis in breast cancer.