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Proteomic profiling reveals that ESR1 mutations enhance cyclin-dependent kinase signaling

Tommaso De Marchi1, Chun-Fui Lai2, Georgia M Simmons2

  • 1Division of Surgery, Oncology, and Pathology, Department of Clinical Sciences, Lund University, Solvegatan 19, 22362, Lund, Sweden. tommaso.de_marchi@med.lu.se.

Scientific Reports
|March 23, 2024
PubMed

Insights

Estrogen receptor (ER) mutations in breast cancer drive proliferation and resistance to endocrine therapy. This study reveals proteomic changes, including immune signaling pathway enrichment, in ER mutant cells, confirming their estrogen-independent growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Proteomics

Background:

  • Estrogen receptor (ER, ESR1 gene) is a key driver in 75% of breast cancers, targeted by endocrine therapies.
  • ESR1 mutations are linked to therapy resistance in metastatic breast cancer, particularly to aromatase inhibitors.
  • While genetic and transcriptomic alterations are studied, protein-level changes in ER mutants remain underexplored.

Purpose of the Study:

  • To investigate protein and phosphoprotein alterations in breast cancer cell lines with common ESR1 mutations (Y537N, Y537S).
  • To characterize proteome-centric differences in ER mutant versus wild-type (wt) ER cells.
  • To understand the mechanisms underlying estrogen-independent proliferation in ER mutant breast cancer.

Main Methods:

  • Utilized an integrated mass spectrometry-based proteomic approach.
  • Analyzed global proteome and phosphoproteome profiles of ER mutant and wt ER breast cancer cell lines.
  • Integrated proteomic and phosphoproteomic data to identify pathway-specific alterations.

Main Results:

  • ER mutant cells showed enrichment of mitotic and immune signaling pathways.
  • Phosphoproteomic analysis revealed increased activity of proliferation-associated kinases, including CDKs and mTOR.
  • Pathway-dependent discrepancies in motility and proliferation were observed between mutant and wt ER cells.
  • Proteomic and phosphorylation patterns confirmed the estrogen-independent phenotype of ER mutant cells.
  • Immune signaling pathways were found to be enriched at the proteomic level in ESR1 mutant models.

Conclusions:

  • This is the first proteome-centric characterization of ESR1 mutant breast cancer models.
  • Confirmed the estrogen-independent growth of ER mutant breast cancer cells.
  • Revealed the significant enrichment of immune signaling pathways in ER mutant cells at the proteomic level.

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