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Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer

Thushangi N Pathiraja1, Shweta R Nayak, Yuanxin Xi

  • 1Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Science Translational Medicine
|March 28, 2014
PubMed

Insights

Aromatase inhibitor resistance in breast cancer involves DNA methylation changes that silence the HOXC10 gene. Long-term treatment can lead to permanent HOXC10 repression, causing resistance and reduced apoptosis.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Aromatase inhibitors (AIs) are crucial for estrogen receptor (ER)-positive breast cancer treatment.
  • Resistance to AIs remains a significant clinical challenge, limiting therapeutic efficacy.
  • Understanding the molecular mechanisms of AI resistance is vital for developing new treatment strategies.

Purpose of the Study:

  • To investigate the epigenetic alterations associated with AI resistance in ER-positive breast cancer.
  • To elucidate the role of the HOXC10 gene in AI resistance.
  • To identify potential therapeutic targets for overcoming AI resistance.

Main Methods:

  • Utilized two breast cancer cell line models of AI resistance.
  • Analyzed DNA methylation patterns, including promoter hypermethylation of developmental genes.
  • Investigated the role of ER binding sites, EZH2, and H3K27me3 in HOXC10 regulation.
  • Examined HOXC10 expression in paired primary and metastatic breast cancer specimens.

Main Results:

  • Identified widespread DNA hyper- and hypomethylation in AI-resistant cells, with enrichment for promoter hypermethylation.
  • Demonstrated that HOXC10 promoter methylation, overlapping an ER binding site, represses HOXC10 expression.
  • Showed that long-term AI treatment leads to increased DNA methylation and silencing of HOXC10 via EZH2 and H3K27me3.
  • Found reduced HOXC10 expression in recurrent tumors from patients treated with AIs, correlating with decreased apoptosis and AI resistance.

Conclusions:

  • Propose a model where estrogen initially represses HOXC10, but AIs initially induce it, leading to apoptosis.
  • Long-term AI treatment causes permanent HOXC10 silencing through epigenetic modifications, conferring resistance.
  • Therapies targeting AI-induced histone and DNA methylation may overcome or delay AI resistance in breast cancer.

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