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SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast

Ylenia Perone1, Aaron J Farrugia2, Alba Rodríguez-Meira1,3

  • 1Department of Surgery and Cancer, Imperial College London, London, UK.

Nature Communications
|May 11, 2019
PubMed

Insights

Drug resistance in ERα breast cancer promotes metastasis. We found Keratin-80 (KRT80) upregulation drives cancer cell invasion and stiffens tumors, linking epigenetic changes to poor survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Estrogen receptor-alpha (ERα) breast cancer recurrence affects 30% of patients after endocrine therapy.
  • The link between endocrine therapy resistance and cancer cell invasiveness remains unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms linking drug resistance to increased invasiveness in ERα breast cancer.
  • To identify potential therapeutic targets for preventing metastasis in resistant breast cancer.

Main Methods:

  • Epigenetic analysis of aromatase inhibitor (AI)-resistant ERα breast cancer cells.
  • Investigated Keratin-80 (KRT80) expression and its regulation by sterol regulatory element-binding protein 1 (SREBP1).
  • Assessed KRT80's role in cytoskeletal dynamics, cell invasion, and tumor stiffness using cell models and patient samples.

Main Results:

  • AI-resistant cells exhibit epigenetic reprogramming of the type II keratin TAD, leading to KRT80 upregulation.
  • SREBP1 activates a de novo enhancer, driving KRT80 expression.
  • KRT80 promotes cytoskeletal rearrangements, focal adhesion, and cellular stiffening, enhancing cancer cell invasion.
  • Patient tumor stiffness correlates with KRT80 levels; increased KRT80 at relapse associates with poor survival.

Conclusions:

  • KRT80 upregulation is a direct consequence of epigenetic reprogramming in AI-resistant breast cancer.
  • KRT80 drives invasion and tumor stiffening, representing a novel link between epigenetic and cytoskeletal changes.
  • KRT80 is a potential therapeutic target for overcoming metastasis in endocrine-resistant breast cancer.

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