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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Estrogen receptors inhibit Smad3 transcriptional activity through Ap-1 transcription factors

Tracy Cherlet1, Leigh C Murphy

  • 1Manitoba Institute of Cell Biology, Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB, Canada R3E 0V9.

Molecular and Cellular Biochemistry
|July 31, 2007
PubMed

Insights

Estrogen receptor (ER) interacts with Smad3, a transforming growth factor beta (TGFβ) mediator, to inhibit breast cancer cell growth. This cross-talk involves c-Jun, impacting TGFβ signaling in breast tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • Breast cancer progression involves dysregulated intracellular signaling, including estrogen receptor (ER) and transforming growth factor beta (TGFβ) pathways.
  • Cross-talk between ER and TGFβ signaling is crucial in breast tumorigenesis, with recent studies highlighting direct interactions.
  • Smad3 is a key downstream mediator of TGFβ signaling, and its interaction with ER warrants further investigation.

Purpose of the Study:

  • To further characterize the cross-talk between ER and TGFβ signaling pathways.
  • To examine the interaction between ER and Smad3, a critical mediator of TGFβ signaling.
  • To elucidate the molecular mechanisms underlying ER's modulation of Smad3 transcriptional activity.

Main Methods:

  • Transient transfection of Cos1 cells with reporter gene constructs (p3TP-lux).
  • Co-transfection experiments involving ERalpha, ERbeta variants, Smad3, and c-Jun/c-Fos.
  • Assessment of transcriptional activity, protein expression, and protein-protein interactions.

Main Results:

  • ERalpha and ERbeta(1) repress Smad3 transcriptional activity in an estradiol-dependent manner, an effect inhibited by antiestrogens.
  • ERbeta(2) and ERbeta(5) variants did not affect Smad3 transcriptional activity.
  • Ligand-bound ER does not alter Smad3 protein levels or directly interact with Smad3; however, c-Jun rescues the inhibitory effect of estrogen on Smad3 activity.

Conclusions:

  • Activated ERalpha and ERbeta(1) inhibit Smad3 transcriptional activity, suggesting a role in regulating TGFβ signaling in breast cancer.
  • The mechanism involves ER sequestering the transcription factor c-Jun, thereby limiting its co-activator function for Smad3.
  • This ER-Smad3 cross-talk, mediated by c-Jun, offers a potential therapeutic target for breast cancer treatment.

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