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Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen

Antoni Hurtado1, Kelly A Holmes, Timothy R Geistlinger

  • 1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

Nature
|November 14, 2008
PubMed

Insights

Estrogen receptor (ER) and tamoxifen complexes directly repress ERBB2 transcription via a cis-regulatory element. The protein PAX2 mediates this repression, influencing tamoxifen response in breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Crosstalk between estrogen receptor (ER) and ERBB2/HER-2 pathways is implicated in breast cancer.
  • A direct transcriptional connection between these pathways has not been established.

Purpose of the Study:

  • To elucidate the direct transcriptional regulation of ERBB2 by ER and tamoxifen.
  • To identify key mediators in the ER-ERBB2 pathway crosstalk relevant to breast cancer treatment response.

Main Methods:

  • Analysis of ERBB2 transcription in human cell lines.
  • Investigation of the role of paired box 2 gene product (PAX2) as a mediator.
  • Assessment of competition between PAX2 and AIB-1/SRC-3 for ERBB2 transcriptional regulation.

Main Results:

  • Estrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription through a gene-specific cis-regulatory element.
  • PAX2 acts as a crucial mediator for ER and tamoxifen-induced ERBB2 repression.
  • PAX2 and ER co-activator AIB-1/SRC-3 compete for ERBB2 regulation, determining tamoxifen response.

Conclusions:

  • The ER-PAX2 interaction provides a mechanistic link between ER-positive and ERBB2-positive breast cancer subtypes.
  • This pathway suggests a mechanism for the progression of ER-positive to aggressive ERBB2-positive tumors.
  • Findings offer insight into endocrine resistance in breast cancer.

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