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Endocrine therapy resistance: new insights

Jonathan T Lei1, Meenakshi Anurag2, Svasti Haricharan3

  • 1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.

Breast (Edinburgh, Scotland)
|December 17, 2019
PubMed

Insights

Estrogen receptor-positive breast cancer deaths are linked to DNA repair defects and acquired mutations. These genetic changes drive endocrine resistance, leading to metastatic disease and treatment failure.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Estrogen receptor-positive (ER+) breast cancer causes over 500,000 global deaths annually, primarily due to endocrine resistance.
  • Endocrine resistance is characterized by high mutation rates and significant subclonal diversity, leading to treatment failure and metastasis.
  • Understanding the mechanisms driving resistance and metastasis is critical for improving patient outcomes.

Purpose of the Study:

  • To investigate the causes of increased mutation rates in lethal ER+ breast cancer.
  • To elucidate the relationship between endocrine therapy resistance and mutational load.
  • To identify the functions of somatic mutations selected in treatment-resistant and metastatic clones.

Main Methods:

  • Analysis of DNA repair defects, specifically single-strand break repair pathways.
  • Investigation of mutations in key cell cycle regulators (ATM, CHK2, CDK4 axis).
  • Identification of acquired mutations, including ESR1 gene fusions, driving metastasis and resistance.

Main Results:

  • Specific defects in single-strand break repair are associated with increased ER+ breast cancer mortality.
  • Loss or mutations of single-strand break repair proteins disrupt estrogen-regulated cell cycle control, directly linking DNA repair defects to endocrine resistance.
  • Acquired mutations, such as in-frame ESR1 gene fusions, promote epithelial-to-mesenchymal transition (EMT)-driven metastasis and endocrine drug-resistant proliferation.

Conclusions:

  • Defects in DNA repair pathways and acquired mutations, including ESR1 fusions, are key drivers of lethal endocrine-resistant ER+ breast cancer.
  • These genetic alterations facilitate both resistance to endocrine therapy and the development of metastatic disease.
  • Targeting DNA repair mechanisms and understanding mutation-driven resistance pathways may offer new therapeutic strategies for ER+ breast cancer.
Keywords:
Breast cancerCancer biomarkersDNA damage repairESR1 fusionsEndocrine therapy resistanceMetastasis

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