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Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both

H H Zhao1, R E Herrera, E Coronado-Heinsohn

  • 1Division of Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA.

The Journal of Biological Chemistry
|May 17, 2001
PubMed

Insights

We identified forkhead homologue in rhabdomyosarcoma (FKHR) as a protein that interacts with estrogen receptors (ER) and other nuclear hormone receptors (NRs). FKHR can act as a coactivator or corepressor, inhibiting breast cancer cell proliferation.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cancer Research

Background:

  • Estrogen receptor (ER) signaling is crucial in breast cancer.
  • Identifying novel ER interacting proteins is key to understanding tamoxifen resistance.
  • Yeast two-hybrid screens are powerful tools for discovering protein-protein interactions.

Purpose of the Study:

  • To identify novel transcriptional intermediary factors for the estrogen receptor (ER).
  • To characterize the function of the identified protein in nuclear hormone receptor (NR) mediated transcription.
  • To investigate the effect of the identified protein on ER-dependent breast cancer cell proliferation.

Main Methods:

  • Yeast two-hybrid screening using ER ligand-binding domain and hinge region as bait.
  • cDNA library derived from tamoxifen-resistant MCF-7 human breast tumors.
  • Transient transfection assays in mammalian cells.
  • Assessment of breast cancer cell proliferation.

Main Results:

  • Isolated and characterized forkhead homologue in rhabdomyosarcoma (FKHR), a NR intermediary protein.
  • FKHR interacts with various NRs, with ligand-dependent and independent interactions.
  • FKHR differentially regulates NR transactivation, acting as a repressor for ER, glucocorticoid receptor, and progesterone receptor.
  • FKHR acts as a coactivator for retinoic acid receptor and thyroid hormone receptor.
  • Overexpression of FKHR inhibits proliferation of ER-dependent MCF-7 breast cancer cells.

Conclusions:

  • FKHR is a bifunctional NR intermediary protein.
  • FKHR can function as either a coactivator or corepressor depending on the specific NR.
  • FKHR's ability to inhibit breast cancer cell proliferation highlights its therapeutic potential.

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