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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Regulation of estrogen-mediated cell survival and proliferation by p160 coactivators

Christopher B Weldon1, Steven Elliott, Yun Zhu

  • 1Department of Surgery, Tulane Cancer Center, New Orleans, LA 70112, USA.

Surgery
|August 10, 2004
PubMed
Abstract

Insights

Estrogen receptor coactivators NCOA-1 and NCOA-3 promote breast cancer cell survival. Inhibiting these coactivator proteins enhances TNF-alpha-induced cell death, suggesting a therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • Estrogen receptor (ER) activity relies on coactivator (CoA) proteins.
  • The specific role of CoA-ER interactions in breast cancer apoptosis is not well understood.

Purpose of the Study:

  • To investigate the role of p160 coactivator family members (NCOA-1, NCOA-2, NCOA-3) in estrogen signaling and breast cancer cell survival.
  • To explore the potential of inhibiting coactivator function as a therapeutic strategy.

Main Methods:

  • Transient transfection of MCF-7 cells with expression vectors for NCOA-1, NCOA-2, or NCOA-3.
  • Assessing cell survival using viability and clonogenic assays.
  • Evaluating estrogen signaling via an estrogen response element (ERE)-luciferase reporter assay.
  • Utilizing dominant-inhibitory (DI)-decoy coactivator constructs to inhibit coactivator function.

Main Results:

  • Overexpression of NCOA-1, NCOA-2, and NCOA-3 significantly enhanced estrogen-mediated gene expression.
  • NCOA-1, NCOA-2, and NCOA-3 overexpression suppressed tumor necrosis factor alpha (TNF-alpha)-induced cell death, promoting cell survival.
  • NCOA-1-mediated survival was confirmed to involve suppression of TNF-alpha-induced apoptosis.
  • DI-decoy-NCOA-1 and DI-decoy-NCOA-3 significantly suppressed clonogenic survival and estrogen-stimulated colony formation, while DI-decoy-NCOA-2 had no significant effect.

Conclusions:

  • NCOA-1 and NCOA-3 overexpression exhibit potent survival effects in breast carcinoma cells.
  • Dominant-inhibitory coactivator constructs increased TNF-alpha-induced cell death and blocked estrogen-induced survival.
  • Inhibiting coactivator proteins presents a viable mechanism for increasing breast cancer sensitivity to therapies.

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