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Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance

Mathieu Lupien1, Clifford A Meyer, Shannon T Bailey

  • 1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Genes & Development
|October 5, 2010
PubMed

Insights

Epidermal growth factor (EGF) activates estrogen receptor alpha (ERα) differently than estrogen, leading to distinct genomic targets. This explains endocrine therapy resistance in ERBB2-positive breast cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Estrogen receptor alpha (ERα) is key in breast cancer endocrine therapy response.
  • Resistance to endocrine therapy is common in ERα-positive tumors overexpressing ERBB2.
  • Growth factors like epidermal growth factor (EGF) can activate ERα independently of estrogen.

Purpose of the Study:

  • To elucidate the mechanism behind stimulus-specific ERα transcriptional programs.
  • To identify the distinct genomic targets (cistromes) of ERα activated by EGF versus estrogen.
  • To understand the role of AP-1 transcription factor in EGF-induced ERα signaling.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-seq) to identify ERα binding sites.
  • Transcriptional profiling to analyze gene expression changes.
  • Analysis of transcription factor AP-1 involvement.

Main Results:

  • EGF-induced ERα genomic targets (cistromes) are distinct from estrogen-induced targets.
  • This EGF-induced ERα cistrome is dependent on the transcription factor AP-1.
  • The EGF-regulated genes are overexpressed in ERBB2-positive human breast cancers.

Conclusions:

  • EGF-induced ERα activation provides a molecular basis for endocrine therapy resistance in ERBB2-positive breast cancers.
  • ERα plays a critical role in hormone-refractory breast tumors driven by growth factor pathways.
  • Therapeutic strategies should consider complete ERα antagonism over solely blocking estrogen responsiveness.

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