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

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.

[1]  Luzhe Sun,et al.  Induction of Transforming Growth Factor-β Receptor Type II Expression in Estrogen Receptor-positive Breast Cancer Cells through SP1 Activation by 5-Aza-2′-deoxycytidine* , 1998, The Journal of Biological Chemistry.

[2]  J. Massagué,et al.  Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer , 2003, Nature Reviews Cancer.

[3]  M. Bennett,et al.  Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. , 1992, Development.

[4]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[5]  A. Ferguson,et al.  The regulation of estrogen receptor expression and function in human breast cancer. , 1998, Cancer treatment and research.

[6]  J. Boulay,et al.  The snail gene required for mesoderm formation in Drosophila is expressed dynamically in derivatives of all three germ layers. , 1991, Development.

[7]  D Pinkel,et al.  Mechanisms of inactivation of E-cadherin in breast cancer cell lines. , 1998, Cancer research.

[8]  Adrian V. Lee,et al.  Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  P. Wade,et al.  Use of bifunctional cross-linking reagents in mapping genomic distribution of chromatin remodeling complexes. , 2004, Methods.

[10]  E. Ballestar,et al.  Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex , 2004, Molecular and Cellular Biology.

[11]  Elaine Fuchs,et al.  A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis , 2004, PLoS biology.

[12]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[13]  M. Levine,et al.  dCtBP mediates transcriptional repression by Knirps, Krüppel and Snail in the Drosophila embryo , 1998, The EMBO journal.

[14]  A. Bosserhoff,et al.  Loss of E-cadherin Expression in Melanoma Cells Involves Up-regulation of the Transcriptional Repressor Snail* , 2001, The Journal of Biological Chemistry.

[15]  A. Howell,et al.  Steroid receptors in human breast cancer , 2004, Trends in Endocrinology & Metabolism.

[16]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[17]  F. Bibeau,et al.  Roles of the Transcription Factors Snail and Slug During Mammary Morphogenesis and Breast Carcinoma Progression , 2004, Journal of Mammary Gland Biology and Neoplasia.

[18]  G. Berx,et al.  Program through Modulation of the Epithelial Cell Differentiation The Transcription Factor Snail Induces Tumor Cell Invasion , 2005 .

[19]  R. Sutherland,et al.  Estrogen regulation of cell cycle progression in breast cancer cells 1 1 Proceedings of the 13th International Symposium of the Journal of Steroid Biochemistry & Molecular Biology “Recent Advances in Steroid Biochemistry & Molecular Biology” Monaco 25–28 May 1997. , 1998, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  En Li,et al.  Suv 39 h-Mediated Histone H 3 Lysine 9 Methylation Directs DNA Methylation to Major Satellite Repeats at Pericentric Heterochromatin , 2003 .

[21]  J. Lis,et al.  Promoter-associated pausing in promoter architecture and postinitiation transcriptional regulation. , 1998, Cold Spring Harbor symposia on quantitative biology.

[22]  P. Wade,et al.  Hormonal regulation of metastasis-associated protein 3 transcription in breast cancer cells. , 2004, Molecular endocrinology.

[23]  J. Wrana,et al.  Regulation of the Polarity Protein Par6 by TGFb Receptors Controls , 2005 .

[24]  E. Carver,et al.  The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition , 2001, Molecular and Cellular Biology.

[25]  P. Wade,et al.  Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress , 2004, Molecular and Cellular Biology.

[26]  J. Foekens,et al.  Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer , 2005, The Lancet.

[27]  P. Dijke,et al.  New insights into TGF-β–Smad signalling , 2004 .

[28]  H. Beug,et al.  TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis , 1998, Current Biology.

[29]  E. Hay,et al.  Cooperation between snail and LEF-1 transcription factors is essential for TGF-beta1-induced epithelial-mesenchymal transition. , 2006, Molecular biology of the cell.

[30]  M. Ozawa,et al.  The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation , 2004, Journal of Cell Science.

[31]  J. Gustafsson,et al.  Estrogen receptor transcription and transactivation: Basic aspects of estrogen action , 2000, Breast Cancer Research.

[32]  K. Korach,et al.  Estrogen receptor null mice: what have we learned and where will they lead us? , 1999, Endocrine reviews.

[33]  J. Ross,et al.  Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  P. Pavasant,et al.  Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays. , 1993, Breast cancer research and treatment.

[35]  J. Herman,et al.  Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells , 2001 .

[36]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

[37]  M. Quintanilla,et al.  Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. , 2003, The Journal of biological chemistry.

[38]  J. Zavadil,et al.  TGF-beta and epithelial-to-mesenchymal transitions. , 2005, Oncogene.

[39]  Y Iwamoto,et al.  A rapid in vitro assay for quantitating the invasive potential of tumor cells. , 1987, Cancer research.

[40]  E. Scanlon,et al.  Growth and metastasis of human breast cancers in athymic nude mice , 2004, Clinical & Experimental Metastasis.

[41]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[42]  A. Muñoz,et al.  SNAIL vs vitamin D receptor expression in colon cancer: therapeutics implications , 2005, British Journal of Cancer.

[43]  S. Sukumar,et al.  Of Snail, mice, and women. , 2005, Cancer cell.

[44]  R. Young,et al.  A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells , 2007, Cell.

[45]  T. Hashimshony,et al.  The role of DNA methylation in setting up chromatin structure during development , 2003, Nature Genetics.

[46]  S. Weiss,et al.  Wnt-dependent Regulation of the E-cadherin Repressor Snail* , 2005, Journal of Biological Chemistry.

[47]  H. Grimes,et al.  Gfi‐1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA‐sensitive mechanism , 2003, Journal of cellular biochemistry.

[48]  J. Thomsen,et al.  Mechanisms of estrogen action. , 2001, Physiological reviews.

[49]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[50]  T. Gridley,et al.  Isolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles during postimplantation development. , 1992, Development.

[51]  Shoichiro Tsukita,et al.  Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail , 2003, Journal of Cell Science.

[52]  Christopher R. Vakoc,et al.  Profile of Histone Lysine Methylation across Transcribed Mammalian Chromatin , 2006, Molecular and Cellular Biology.

[53]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[54]  J. Willson,et al.  Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells , 1994 .

[55]  K. Korach,et al.  Estrogen receptors and human disease. , 2006, The Journal of clinical investigation.

[56]  M. Mareel,et al.  Internalization of the E-Cadherin/Catenin Complex and Scattering of Human Mammary Carcinoma Cells MCF-7/AZ after Treatment with Conditioned Medium from Human Skin Squamous Carcinoma Cells COLO 16 , 2000, Cell adhesion and communication.

[57]  H. Kawai,et al.  Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α , 2003, International journal of cancer.

[58]  S. Nass,et al.  The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[59]  Carlos S. Moreno,et al.  MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast Cancer , 2003, Cell.

[60]  G. Laurie,et al.  Basement membrane complexes with biological activity. , 1986, Biochemistry.

[61]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[62]  J. Willson,et al.  Defects of TGF-β receptor signaling in mammary cell tumorigenesis , 1996, Journal of Mammary Gland Biology and Neoplasia.

[63]  E. Hay,et al.  Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells , 1982, The Journal of cell biology.

[64]  C. Allis,et al.  Linking the epigenetic ‘language’ of covalent histone modifications to cancer , 2004, British Journal of Cancer.

[65]  S. Baylin,et al.  Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. , 1994, Cancer research.

[66]  Donald P. McDonnell,et al.  Connections and Regulation of the Human Estrogen Receptor , 2002, Science.

[67]  Adrian V. Lee,et al.  Constitutively Active Type I Insulin-Like Growth Factor Receptor Causes Transformation and Xenograft Growth of Immortalized Mammary Epithelial Cells and Is Accompanied by an Epithelial-to-Mesenchymal Transition Mediated by NF-κB and Snail , 2007, Molecular and Cellular Biology.

[68]  M. J. van de Vijver,et al.  Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. , 2006, Journal of the National Cancer Institute.