Transcription factor EGR 3 is involved in the estrogen-signaling pathway in breast cancer cells

Estrogen has been closely associated with the genesis and malignant progression of breast cancer. However, the molecular mechanism underlying the effects of estrogen is far from being completely clarified. We previously developed a custom-made cDNA microarray consisting of approximately 200 estrogen-responsive genes in breast cancer cells. Using this system, we found one estrogen-induced gene in various cancer cell lines, including breast cancer MCF-7 cells, which encode a zinc-finger transcription factor, EGR3 (early growth response 3). Northern blot analysis of estradiol-treated MCF-7 cells showed rapid and robust induction of Egr3, and addition of cycloheximide or ICI 182,780 suggested that Egr3 is the bona fide target for the estrogen receptor (ER ). Using stable transformants derived from MCF-7 cells which were transfected with expression-controllable Egr3-expression vector, we demonstrated that Nab2 is one of the target genes for EGR3. Microarray analysis of the transformants revealed other candidate EGR3-induced genes. These strategies could be useful for analyzing downstream genes of ER , and may contribute to elucidating the extensive signaling network of estrogen stimuli. Furthermore, a reporter assay using the upstream region of fasL probably involving escape from the immune system revealed that fasL is another target gene for EGR3. The roles of EGR3 in the physiology of breast cancer are discussed. Journal of Molecular Endocrinology (2004) 32, 649–661

[1]  T. Yamori,et al.  Development of cDNA microarray for expression profiling of estrogen-responsive genes. , 2002, Journal of molecular endocrinology.

[2]  Sara J. Prest,et al.  The estrogen‐regulated protein, TFF1, stimulates migration of human breast cancer cells , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  Melissa C Southey,et al.  Stanniocalcin 2 is an estrogen-responsive gene coexpressed with the estrogen receptor in human breast cancer. , 2002, Cancer research.

[4]  M. Schumacher,et al.  Early activation of transcription factor expression in Schwann cells by progesterone. , 2001, Brain research. Molecular brain research.

[5]  M. Parker,et al.  Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling. , 2001, Journal of molecular endocrinology.

[6]  David Botstein,et al.  RERG Is a Novel ras-related, Estrogen-regulated and Growth-inhibitory Gene in Breast Cancer* , 2001, The Journal of Biological Chemistry.

[7]  C. Keller-Peck,et al.  The transcription factor Egr3 modulates sensory axon-myotube interactions during muscle spindle morphogenesis. , 2001, Developmental biology.

[8]  A Orimo,et al.  Efp as a primary estrogen‐responsive gene in human breast cancer , 2000, FEBS letters.

[9]  J. Milbrandt,et al.  A Novel Activation Function for NAB Proteins in EGR-dependent Transcription of the Luteinizing Hormone β Gene* , 2000, The Journal of Biological Chemistry.

[10]  S. Safe,et al.  Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition. , 1999, Molecular endocrinology.

[11]  J. Sloane,et al.  Oestrogen receptor expression in the normal and pre‐cancerous breast , 1999, The Journal of pathology.

[12]  G. Mor,et al.  The Fas/Fas‐ligand system: a mechanism for immune evasion in human breast carcinomas , 1999, Breast Cancer Research and Treatment.

[13]  J. Baraban,et al.  The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience , 1999, Trends in Neurosciences.

[14]  J. Milbrandt,et al.  Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3 , 1998, Nature Genetics.

[15]  J. Milbrandt,et al.  The Transcriptional Corepressor NAB2 Inhibits NGF-induced Differentiation of PC12 Cells , 1998, The Journal of cell biology.

[16]  Y. Nakamura,et al.  Isolation and characterization of a novel human lung-specific gene homologous to lysosomal membrane glycoproteins 1 and 2: significantly increased expression in cancers of various tissues. , 1998, Cancer research.

[17]  J. Ashwell,et al.  Cyclosporin A-Sensitive Transcription Factor Egr-3 Regulates Fas Ligand Expression , 1998, Molecular and Cellular Biology.

[18]  T. Whiteside,et al.  Lymphocyte apoptosis induced by Fas ligand- expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes. , 1998, The Journal of clinical investigation.

[19]  J. Baraban,et al.  Sequential Expression of Egr‐1 and Egr‐3 in Hippocampal Granule Cells Following Electroconvulsive Stimulation , 1998, Journal of neurochemistry.

[20]  Andrew D. Badley,et al.  Transcriptional Regulation of the Human FasL Promoter-Enhancer Region* , 1998, The Journal of Biological Chemistry.

[21]  M. Mayo,et al.  Basic fibroblast growth factor transcriptional autoregulation requires EGR-1 , 1997, Oncogene.

[22]  T. Kurihara,et al.  Two promoters in expression of estrogen receptor messenger RNA in human breast cancer. , 1997, Carcinogenesis.

[23]  J. Milbrandt,et al.  NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli , 1996, Molecular and cellular biology.

[24]  K. Kirsch,et al.  Mader: a novel nuclear protein over expressed in human melanomas. , 1996, Oncogene.

[25]  J. Milbrandt,et al.  Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  V. Sukhatme,et al.  cDNA sequence of the human cellular early growth response gene Egr-1. , 1990, Nucleic acids research.

[27]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[28]  P. Chambon,et al.  Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Chambon,et al.  Cloning of cDNA sequences of hormone-regulated genes from the MCF-7 human breast cancer cell line. , 1982, Nucleic acids research.

[30]  H. Rochefort,et al.  A secreted glycoprotein induced by estrogen in human breast cancer cell lines , 1980, Cell.

[31]  J. Zwiller,et al.  Differential rat brain expression of EGR proteins and of the transcriptional corepressor NAB in response to acute or chronic cocaine administration , 2007, NeuroMolecular Medicine.

[32]  F. Gago,et al.  Estrogen receptors, progesterone receptors, and cell proliferation in human breast cancer , 2005, Breast Cancer Research and Treatment.

[33]  A. Howell,et al.  Estrogen Responsiveness and Control of Normal Human Breast Proliferation , 2004, Journal of Mammary Gland Biology and Neoplasia.

[34]  Satoshi Inoue,et al.  Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. , 2002, Nature.

[35]  V. Sukhatme,et al.  Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. , 1995, Progress in nucleic acid research and molecular biology.

[36]  R. Bravo,et al.  Expression of PILOT, a putative transcription factor, requires two signals and is cyclosporin A sensitive in T cells. , 1993, International immunology.

[37]  M. Pike,et al.  Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. , 1993, Epidemiologic reviews.

[38]  M. Rio,et al.  Structure and function of the pS2 gene and estrogen receptor in human breast cancer cells. , 1988, Cancer treatment and research.