Estrogen-regulated gene networks in human breast cancer cells: Involvement of E2F1 in the regulation of cell proliferation

Joshua D. Stender, Jonna Frasor, Barry Komm, Ken C N Chang, W. Lee Kraus, Benita S Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Estrogens generally stimulate the proliferation of estrogen receptor (ER)-containing breast cancer cells, but they also suppress proliferation of some ER-positive breast tumors. Using a genome-wide analysis of gene expression in two ER-positive human breast cancer cell lines that differ in their proliferative response to estrogen, we sought to identify genes involved in estrogen-regulated cell proliferation. To this end, we compared the transcriptional profiles of MCF-7 and MDA-MB-231ER+ cells, which have directionally opposite 17β-estradiol (E2)-dependent proliferation patterns, MCF-7 cells being stimulated and 231ER+ cells suppressed by E2. We identified a set of approximately 70 genes regulated by E2 in both cells, with most being regulated by hormone in an opposite fashion. Using a variety of bioinformatics approaches, we found the E2F binding site to be overrepresented in the potential regulatory regions of many cell cycle-related genes stimulated by estrogen in MCF-7 but inhibited by estrogen in 231ER+ cells. Biochemical analyses confirmed that E2F1 and E2F downstream target genes were increased in MCF-7 and decreased in 231ER+ cells upon estrogen treatment. Furthermore, RNA interference-mediated knockdown of E2F1 blocked estrogen regulation of E2F1 target genes and resulted in loss of estrogen regulation of proliferation. These results demonstrate that regulation by estrogen of E2F1, and subsequently its downstream target genes, is critical for hormone regulation of the proliferative program of these breast cancer cells, and that gene expression profiling combined with bioinformatic analyses of transcription factor binding site enrichment in regulated genes can identify key components associated with nuclear receptor hormonal regulation of important cellular functions.

Original languageEnglish (US)
Pages (from-to)2112-2123
Number of pages12
JournalMolecular Endocrinology
Volume21
Issue number9
DOIs
StatePublished - Sep 1 2007

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Gene Regulatory Networks
Estrogens
Cell Proliferation
Breast Neoplasms
Estrogen Receptors
Genes
Computational Biology
Binding Sites
Hormones
cdc Genes
Nucleic Acid Regulatory Sequences
Neoplasm Genes
MCF-7 Cells
Gene Expression Profiling
Cytoplasmic and Nuclear Receptors
RNA Interference
Estradiol
Transcription Factors
Genome
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Estrogen-regulated gene networks in human breast cancer cells : Involvement of E2F1 in the regulation of cell proliferation. / Stender, Joshua D.; Frasor, Jonna; Komm, Barry; Chang, Ken C N; Kraus, W. Lee; Katzenellenbogen, Benita S.

In: Molecular Endocrinology, Vol. 21, No. 9, 01.09.2007, p. 2112-2123.

Research output: Contribution to journalArticle

Stender, Joshua D. ; Frasor, Jonna ; Komm, Barry ; Chang, Ken C N ; Kraus, W. Lee ; Katzenellenbogen, Benita S. / Estrogen-regulated gene networks in human breast cancer cells : Involvement of E2F1 in the regulation of cell proliferation. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 9. pp. 2112-2123.
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