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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

Steroid hormone modulation of RET through two estrogen responsive enhancers in breast cancer

Zachary E Stine1, David M McGaughey, Seneca L Bessling

  • 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.

Human Molecular Genetics
|July 9, 2011
PubMed

Insights

Estrogen (E2) and retinoic acid (RA) cooperatively regulate RET gene expression in breast cancer. Estrogen receptor-alpha (ESR1) is crucial for E2-induced RET transcription, acting on specific regulatory elements.

Area of Science:

  • Molecular biology
  • Genetics
  • Endocrinology

Background:

  • The RET gene is implicated in breast cancer progression, specifically estrogen independence and tamoxifen resistance.
  • RET gene expression is modulated by both estrogen (E2) and retinoic acid (RA) in breast cancer cells.
  • The precise regulatory elements mediating steroid hormone transcriptional control of RET are not well understood.

Purpose of the Study:

  • To identify and characterize the regulatory elements controlling RET gene transcription in response to E2 and RA.
  • To elucidate the role of estrogen receptor-alpha (ESR1) in mediating E2-dependent RET regulation.
  • To investigate the functional significance of identified regulatory elements in vivo.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to identify potential ESR1 and RA receptor binding sites at the RET locus.
  • Reporter gene assays in MCF-7 breast cancer cells to assess the regulatory activity of RET gene promoter/enhancer regions.
  • Site-directed mutagenesis to identify key sequences within regulatory elements responsible for E2 responsiveness.
  • Zebrafish transgenesis to evaluate the in vivo expression pattern directed by RET regulatory elements.

Main Results:

  • Two specific regulatory elements, RET -49.8 and RET +32.8, were identified as significantly responsive to E2.
  • Endogenous RET expression and the activity of the RET -49.8 element are cooperatively regulated by E2 and RA.
  • Key sequences within RET -49.8 and RET +32.8, including ESR1, FOXA1, and TFAP2C binding motifs, are essential for E2 responsiveness.
  • ESR1 is indispensable for E2-induced RET expression and enhancer activity, demonstrating its sufficiency in mediating this regulation.
  • Zebrafish studies confirmed that RET -49.8 directs reporter expression in the central and peripheral nervous systems.

Conclusions:

  • RET transcription in breast cancer is modulated by E2 through ESR1 acting on multiple regulatory elements.
  • The identified regulatory elements and the role of ESR1 provide novel insights into the mechanisms of RET gene control in breast cancer.
  • These findings highlight potential therapeutic targets for managing breast cancer driven by RET signaling.

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