Abstract
Estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation and also through the biological functions of target loci. Here, we identify the product of human MTA3 as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrate that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. These results establish a mechanistic link between estrogen receptor status and invasive growth of breast cancers.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence / genetics
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Base Sequence / genetics
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Cadherins / genetics
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Cadherins / metabolism
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Carcinoma / genetics*
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Carcinoma / metabolism
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Cell Differentiation / genetics
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Cell Division / genetics
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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DNA Mutational Analysis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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Gene Expression Regulation, Neoplastic / genetics*
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HeLa Cells
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
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Molecular Sequence Data
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Repressor Proteins / genetics
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation
Substances
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Cadherins
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DNA-Binding Proteins
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MTA3 protein, human
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Neoplasm Proteins
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Receptors, Estrogen
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Repressor Proteins
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Snail Family Transcription Factors
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Transcription Factors
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Histone Deacetylases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex