The estrogen-regulated transcription factor PITX1 coordinates gene-specific regulation by estrogen receptor-alpha in breast cancer cells

Joshua D. Stender, Fabio Stossi, Cory C. Funk, Tze Howe Charn, Daniel H. Barnett, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

The estrogen receptor α (ERα) is a master regulator of gene expression and works along with cooperating transcription factors in mediating the actions of the hormone estradiol (E2) in ER-positive tissues and breast tumors. Here, we report that expression of paired-like homeodomain transcription factor (PITX1), a tumor suppressor and member of the homeobox family of transcription factors, is robustly up-regulated by E2 in several ERα-positive breast cancer cell lines via ERα-dependent interaction between the proximal promoter and an enhancer region 5' upstream of the PITX1 gene. Overexpression of PITX1 selectively inhibited the transcriptional activity of ERα and ERβ, while enhancing the activities of the glucocorticoid receptor and progesterone receptor. Reduction of PITX1 by small interfering RNA enhanced ERα-dependent transcriptional regulation of a subset of ERα target genes. The consensus PITX1 binding motif was found to be present in 28% of genome-wide ERα binding sites and was in close proximity to estrogen response elements in a subset of ERα binding sites, and E2 treatment enhanced PITX1 as well as ERα recruitment to these binding sites. These studies identify PITX1 as a new ERα transcriptional target that acts as a repressor to coordinate and fine tune target-specific, ERα-mediated transcriptional activity in human breast cancer cells.

Original languageEnglish (US)
Pages (from-to)1699-1709
Number of pages11
JournalMolecular Endocrinology
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2011

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Estrogen Receptor alpha
Estrogen Receptors
Estrogens
Transcription Factors
Breast Neoplasms
Genes
Binding Sites
Homeobox Genes
Glucocorticoid Receptors
Response Elements
Progesterone Receptors
Regulator Genes
Genetic Promoter Regions
Human Activities
Small Interfering RNA
Estradiol
Consensus

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

The estrogen-regulated transcription factor PITX1 coordinates gene-specific regulation by estrogen receptor-alpha in breast cancer cells. / Stender, Joshua D.; Stossi, Fabio; Funk, Cory C.; Charn, Tze Howe; Barnett, Daniel H.; Katzenellenbogen, Benita S.

In: Molecular Endocrinology, Vol. 25, No. 10, 01.10.2011, p. 1699-1709.

Research output: Contribution to journalArticle

Stender, Joshua D. ; Stossi, Fabio ; Funk, Cory C. ; Charn, Tze Howe ; Barnett, Daniel H. ; Katzenellenbogen, Benita S. / The estrogen-regulated transcription factor PITX1 coordinates gene-specific regulation by estrogen receptor-alpha in breast cancer cells. In: Molecular Endocrinology. 2011 ; Vol. 25, No. 10. pp. 1699-1709.
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