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FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance

Y Yu-Rice1, Y Jin1, B Han1

  • 1Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Oncogene
|April 5, 2016
PubMed

Insights

FOXC1 suppresses estrogen receptor-alpha (ERα) in breast cancer by competing with GATA3. This mechanism explains low ERα in basal-like breast cancer and predicts reduced response to endocrine therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Endocrinology

Background:

  • Estrogen receptor-alpha (ERα) is crucial for estrogen's role in breast development and cancer.
  • ERα regulation is well-studied in luminal and HER2-positive breast cancer, but less so in basal-like breast cancer (BLBC).
  • Mechanisms for ERα loss in recurrent tumors after endocrine therapy are unclear.

Purpose of the Study:

  • To identify a novel mechanism for ERα suppression in breast cancer.
  • To investigate the role of FOXC1 in regulating ERα expression.
  • To explore the clinical relevance of FOXC1 in breast cancer progression and endocrine therapy response.

Main Methods:

  • Investigated FOXC1's interaction with ERα cis-regulatory elements.
  • Assessed FOXC1's competition with GATA3 for DNA binding.
  • Examined the impact of FOXC1 on RNA polymerase II recruitment and histone modifications at ERα promoters.
  • Evaluated the effect of ectopic FOXC1 expression on breast cancer cell sensitivity to estrogen and tamoxifen.
  • Correlated FOXC1 expression with ER expression in recurrent tumors from patients treated with tamoxifen.

Main Results:

  • FOXC1 suppresses ERα expression by competing with GATA3 for binding sites.
  • FOXC1's forkhead domain is essential for this competitive DNA binding.
  • Overexpression of FOXC1 reduces ERα transcriptional activity by hindering RNA polymerase II and increasing H3K9 trimethylation.
  • Ectopic FOXC1 expression decreased sensitivity to estrogen and tamoxifen in luminal breast cancer cells.
  • High FOXC1 expression in primary tumors correlated with decreased ER expression in recurrent tumors after tamoxifen treatment.

Conclusions:

  • FOXC1-driven suppression of ERα is a novel mechanism contributing to low ERα in BLBC.
  • FOXC1 plays a role in modulating cellular response to endocrine therapy.
  • This study provides a new perspective on ERα regulation in breast cancer progression.

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