Endocrine therapy resistance: new insights

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.