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The Transcription Factor Snail Mediates Epithelial to Mesenchymal Transitions by Repression of Estrogen Receptor-

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Paul A. Wade, Ph.D., Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709. E-mail: wadep2{at}niehs.nih.gov.

The estrogen receptor (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 after 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 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--positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Furthermore, 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 TGF-β signaling pathway. Thus, cross-talk among ER-, Snail, and the TGF-β pathway appears to control critical phenotypic properties of breast cancer cells.

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Nuclear Receptors:   ERα