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

The RET tyrosine kinase signaling pathway is involved in the development of endocrine resistant ER+ breast cancer. However, the expression of the RET receptor itself has not been directly linked to clinical cases of resistance, suggesting that additional factors are involved. We show that both ER+ endocrine resistant and sensitive breast cancers have functional RET tyrosine kinase signaling pathway, but that endocrine sensitive breast cancer cells lack RET ligands that are necessary to drive endocrine resistance. Transcription of one RET ligand, GDNF, is necessary and sufficient to confer resistance in the ER+ MCF-7 cell line. In patients, RET ligand expression predicts responsiveness to endocrine therapies and correlates with survival. Collectively, our findings show that ER+ tumor cells are \"poised\" for RET mediated endocrine resistance, expressing all components of the RET signaling pathway, but endocrine sensitive cells lack high expression of RET ligands that are necessary to initiate the resistance phenotype.