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PMID: 17761946 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha.

Molecular endocrinology (Baltimore, Md.) ·Vol. 21 ·No. 12 ·2007-12-00 ·Pages 2907-18

Dhasarathy A, Kajita M, Wade PA

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.

MeSH Terms
Acetylation Breast Neoplasms/metabolism Cell Differentiation Cell Line, Tumor Down-Regulation Epithelial Cells/cytology,metabolism Estrogen Receptor alpha/genetics,metabolism Histones/metabolism Humans Introns/genetics Mesenchymal Stem Cells/cytology,metabolism Microarray Analysis Phenotype Promoter Regions, Genetic/genetics Protein Binding Signal Transduction Snail Family Transcription Factors Transcription Factors/genetics,metabolism Transcription, Genetic/genetics Transforming Growth Factor beta/metabolism
Chemicals
ESR1 protein, human Estrogen Receptor alpha Histones Snail Family Transcription Factors Transcription Factors Transforming Growth Factor beta
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dhasarathy Archana
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, P.O. Box 12233, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709, USA.
Kajita Masahiro
Wade Paul A
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Article Info
Journal
Molecular endocrinology (Baltimore, Md.)
Abbr.
Mol Endocrinol
ISSN
0888-8809
DOI
10.1210/me.2007-0293
Published
2007-12-00
Epub
2007-00-30
Pages
2907-18
Language
English
Region
United States
NLM ID
8801431
PMCID
PMC2668600
Subset
IM
Grants
Intramural NIH HHS · Z01 ES101965-03 · United States
External Links
PubMed source DOI: 10.1210/me.2007-0293 PMC Full Text View journal details
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