The estrogen receptor-alpha (ER-, ESR1) is a key regulatory molecule in mammary epithelial cell development. Loss of ER- in breast cancer is correlated with poor prognosis, increased recurrence following treatment, and an elevated incidence of metastasis. A proposed molecular pathway by which ER- acts to constrain invasive growth in breast cancer cells involves direct, ER- dependent expression of MTA3, a cell-type specific component of the Mi-2/NuRD chromatin remodeling complex. MTA3 in turn represses expression of Snail, a transcription factor linked to epithelial to mesenchymal transition (EMT) and cancer metastasis. To elucidate its role(s) in EMT, we expressed Snail in the non-invasive, ER- positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Further, we observed loss of ER- expression at both the RNA and protein level that was accompanied by direct interaction of Snail with regulatory DNA sequences at the ESR1 locus. A consequence of loss of ER- function in this system was the increased abundance of key components of the transforming growth factor- (TGF-) signaling pathway. Thus, cross-talk between ER-, Snail and the TGF- pathway appears to control critical phenotypic properties of breast cancer cells.