Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

Bridgette M. Collins-Burow, James W. Antoon, Daniel E. Frigo, Steven Elliott, Christopher B. Weldon, Stephen M. Boue, Barbara S. Beckman, Tyler J. Curiel, Jawed Alam, John A. McLachlan, Matthew E. Burow

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling independent of direct receptor binding. Here we demonstrate both chalcone and flavone function as cell type-specific selective ER modulators. In MCF-7 breast carcinoma cells chalcone and flavone suppress ERα activity through stimulation of the stress-activated members of the mitogen-activated protein kinase (MAPK) family: c-Jun N-terminal kinase (JNK)1 and JNK2. The use of dominant-negative mutants of JNK1 or JNK2 in stable transfected cells established that the antiestrogenic effects of chalcone and flavone required intact JNK signaling. We further show that constitutive activation of the JNK pathway partially suppresses estrogen (E2)-mediated gene expression in breast, but not endometrial carcinoma cells. Our results demonstrate a role for stress-activated MAPKs in the cell type-specific regulation of ERα function.

Original languageEnglish (US)
Pages (from-to)186-193
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume132
Issue number1-2
DOIs
StatePublished - Oct 1 2012

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Keywords

  • Antiestrogens
  • Estrogen receptor
  • Flavonoids
  • Mitogen-activated protein kinase
  • Phytoestrogens
  • c-Jun N-terminal kinase (JNK)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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