The Role of Nesprin-4 in Breast Cancer Migration and Invasion

Cancer metastasis is responsible for most cancer-related deaths. Migration and invasion, key steps in the metastatic cascade, require nuclear pliability to traverse the physical barriers of the extracellular matrix and cell–cell junctions. The nuclear envelope (NE) contains LINC complex proteins, including nesprin-4, which regulate nuclear integrity, stiffness, and cell movement. We report that nesprin-4 expression is generally upregulated in breast cancer samples but is reduced in triple-negative breast cancer (TNBC) samples compared to other subtypes. A nesprin-4 expression analysis in 62 breast cancer cell lines showed that nesprin-4 expression correlates positively with cell lines representing less aggressive tumors, while TNBC cell lines have low or no nesprin-4 expression. To determine the role of nesprin-4, we modulated nesprin-4 expression levels in three breast cancer cell lines: MCF7, T47D (luminal A and nesprin-4-positive), and MDA-MB-231 (TNBC and nesprin-4-negative). We found that nesprin-4 promotes migration and invasion by driving cell polarization. However, we also found that nesprin-4 impedes intravasation into endothelial microvessels. Thus, we propose that nesprin-4 plays a dual role in breast cancer, promoting efficient migration and invasion, but blocking intravasation.