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

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Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant

Joanna Achinger-Kawecka1,2, Fatima Valdes-Mora1,2, Phuc-Loi Luu1,2

  • 1Epigenetics Research Laboratory, Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.

Nature Communications
|January 18, 2020
PubMed

Insights

3D chromatin interactions change in endocrine-resistant estrogen receptor-positive breast cancer. This 3D epigenome remodeling, involving altered enhancers, promoters, and gene expression, is a key mechanism driving resistance.

Area of Science:

  • Genomics
  • Epigenetics
  • Cancer Biology

Background:

  • Endocrine therapy resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer.
  • The molecular mechanisms driving this resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of 3D chromatin interactions in the development of endocrine resistance in ER+ breast cancer.

Main Methods:

  • Analysis of 3D chromatin interactions within and between topologically associating domains (TADs) in endocrine-resistant ER+ breast cancer cells.
  • Identification of genetic variants at CTCF-bound anchors and their association with differential interactions.
  • Assessment of enhancer and promoter activity, ER binding sites, and gene expression alterations.

Main Results:

  • Significant changes in 3D chromatin interactions were observed in endocrine-resistant cells.
  • Differential interactions were enriched for resistance-associated genetic variants at CTCF-bound anchors.
  • Ectopic interactions correlated with altered ER-regulated gene expression, suggesting dynamic pathway remodeling.
  • Loss of interactions coincided with hypermethylation and reduced ER binding.
  • Alterations in chromosomal compartments (A and B) were linked to decreased ER binding and atypical gene expression.

Conclusions:

  • 3D epigenome remodeling, including changes in chromatin interactions and chromosomal compartments, is a critical mechanism underlying endocrine resistance in ER+ breast cancer.
  • These epigenetic alterations impact ER binding, enhancer/promoter activity, and gene expression, contributing to therapeutic failure.

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