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Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1

Jean McBryan1, Sarah M Theissen, Christopher Byrne

  • 1Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.

Cancer Research
|November 24, 2011
PubMed

Insights

Aromatase inhibitor resistance in breast cancer involves hormone receptor switching and increased cell migration. Steroid receptor coactivator SRC-1 and Ets2 interaction drives this aggressive, endocrine-independent progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Aromatase inhibitors (AIs) are standard treatment for estrogen receptor-positive breast cancer.
  • Mechanisms of acquired resistance to AIs are not fully understood.
  • Tumor recurrence during AI therapy necessitates research into resistance pathways.

Purpose of the Study:

  • Investigate mechanisms of acquired resistance to Aromatase Inhibitors (AIs) in breast cancer.
  • Identify molecular players driving endocrine-independent progression and metastasis.
  • Correlate specific molecular markers with patient outcomes.

Main Methods:

  • Analysis of patient cohorts treated with AIs.
  • Development and study of a letrozole-resistant cell line model.
  • Assessment of hormone receptor status, cell phenotype, and gene expression.
  • Investigation of protein-protein interactions (SRC-1 and Ets2).

Main Results:

  • Hormone receptor switching observed in recurrent tumors from AI-treated patients.
  • Resistant cells showed endocrine-independent, growth factor-responsive growth with increased migration.
  • High expression of Steroid Receptor Coactivator-1 (SRC-1) in resistant cells and patient tumors.
  • SRC-1 and Ets2 interaction regulated Myc and MMP9, driving aggressive phenotypes.
  • Increased SRC-1 expression correlated with reduced disease-free survival.

Conclusions:

  • Aromatase inhibitor resistance involves hormone receptor switching and dedifferentiation.
  • The SRC-1/Ets2 complex promotes aggressive, migratory phenotypes in endocrine-resistant breast cancer.
  • This pathway represents a mechanism for AI-specific metastatic progression.

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