Loss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin

Oestrogen receptor alpha (ER alpha) is a well-known target of endocrine therapy for ER alpha-positive breast cancer. ER alpha-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse. Here we determine that loss of ERa in the invasive front and in lymph node metastasis in human breast cancer is significantly correlated with lymphatic metastasis. Using in vivo and in vitro experiments, we demonstrate that ERa inhibits breast cancer metastasis. Furthermore, we find that ER alpha is a novel regulator of vinculin expression in breast cancer. Notably, ERa suppresses the amoeboid-like movement of breast cancer cells by upregulating vinculin in 3D matrix, which in turn promotes cell-cell and cell-matrix adhesion and inhibits the formation of amoeboid-like protrusions. A positive association between ER alpha and vinculin expression is found in human breast cancer tissues. The results show that ER alpha inhibits breast cancer metastasis and suggest that ERa suppresses cell amoeboid-like movement by upregulating vinculin.