ERE-independent ERα target genes differentially expressed in human breast tumors

Christine Glidewell-Kenney, Jeffrey Weiss, Eun Jig Lee, Suresh Pillai, Toshio Ishikawa, Eric A. Ariazi, J. Larry Jameson*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERα can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-κB) at their cognate sites on DNA. We previously generated a mutant form of ERα (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERα into MDA-MB231 ERα-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17β-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERα pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERα responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERα pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERα target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.

Original languageEnglish (US)
Pages (from-to)53-59
Number of pages7
JournalMolecular and Cellular Endocrinology
Volume245
Issue number1-2
DOIs
StatePublished - Dec 21 2005

Keywords

  • Estrogen receptor alpha
  • Microarray (human breast tumor)
  • Nonclassical
  • SERM

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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  • Cite this

    Glidewell-Kenney, C., Weiss, J., Lee, E. J., Pillai, S., Ishikawa, T., Ariazi, E. A., & Jameson, J. L. (2005). ERE-independent ERα target genes differentially expressed in human breast tumors. Molecular and Cellular Endocrinology, 245(1-2), 53-59. https://doi.org/10.1016/j.mce.2005.10.003