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ER-positive breast cancer cells are poised for RET-mediated endocrine resistance

Sachi Horibata1,2, Edward J Rice1, Chinatsu Mukai1

  • 1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.

Plos One
|April 3, 2018
PubMed

Insights

Estrogen receptor-positive (ER+) breast cancer cells are poised for RET signaling-mediated endocrine resistance. Lack of RET ligands like GDNF in sensitive cells prevents resistance, while their presence drives it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • The RET tyrosine kinase signaling pathway plays a role in endocrine-resistant ER+ breast cancer.
  • The precise mechanisms by which ER+ cells activate RET signaling and develop endocrine resistance are not fully understood.

Purpose of the Study:

  • To investigate how ER+ breast cancer cells activate RET signaling.
  • To identify the role of RET ligands in the development of endocrine resistance.
  • To determine if RET ligand expression can predict patient response to endocrine therapy.

Main Methods:

  • Analysis of RET tyrosine kinase signaling pathway components in ER+ endocrine-resistant and sensitive breast cancer cells.
  • Investigating the necessity and sufficiency of Glial cell line-derived neurotrophic factor (GDNF) in conferring endocrine resistance.
  • Assessing the impact of endogenous GDNF production, translation, and secretion on RET signaling.
  • Correlating RET ligand expression with patient responsiveness to endocrine therapies and survival rates.

Main Results:

  • Both endocrine-resistant and sensitive ER+ breast cancers possess a functional RET tyrosine kinase signaling pathway.
  • Endocrine-sensitive breast cancer cells lack the necessary RET ligands to drive endocrine resistance.
  • Transcription of GDNF is both necessary and sufficient to confer endocrine resistance in ER+ MCF-7 cells.
  • Endogenous GDNF produced by resistant cells activates RET signaling in adjacent cells.
  • RET ligand expression in patients predicts endocrine therapy responsiveness and correlates with survival.

Conclusions:

  • ER+ breast cancer cells express all components of the RET signaling pathway, remaining 'poised' for RET-mediated endocrine resistance.
  • High expression of RET ligands, such as GDNF, is crucial for initiating the endocrine-resistant phenotype in ER+ breast cancer.
  • RET ligand expression serves as a predictive biomarker for endocrine therapy outcomes in breast cancer patients.

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