Metastasis is one of the major causes of endocrine resistance and mortality in breast cancer patients. The epithelial to mesenchymal transition (EMT) enables the metastatic spread of cancer cells. EMT-promoting transcription factors determine a continuum of different EMT states. In contrast, estrogen receptor α (ERα) contributes to the maintenance of the epithelial phenotype of breast cancer cells and is crucial for effective hormonal therapies. Determining whether and how the EMT modulates ERα signaling at early stage of EMT could drive the discovery of novel therapeutic approaches to prevent or to fight metastasis. We have discovered that during EMT initiation the expression of ZEB1 modulates ERα-mediated transcription induced by estrogen or cAMP signaling in breast cancer cells. We discovered that a cooperative interaction between ZEB1 and ERα is important for modulating tissue tropism of breast cancer cells towards bone metastasis.