Abstract
The estrogen receptor (ER)-alpha (ESR1) is a key regulatory molecule in mammary epithelial cell development. Loss of ER-alpha in breast cancer is correlated with poor prognosis, increased recurrence after treatment, and an elevated incidence of metastasis. A proposed molecular pathway by which ER-alpha acts to constrain invasive growth in breast cancer cells involves direct, ER-alpha-dependent expression of metastasis-associated protein 3, 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 and cancer metastasis. To elucidate its role(s) in epithelial to mesenchymal transition (EMT), we expressed Snail in the noninvasive, ER-alpha-positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Furthermore, we observed loss of ER-alpha 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-alpha function in this system was the increased abundance of key components of the TGF-beta signaling pathway. Thus, cross-talk among ER-alpha, Snail, and the TGF-beta pathway appears to control critical phenotypic properties of breast cancer cells.