TY - JOUR T1 - RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ERα JF - bioRxiv DO - 10.1101/098848 SP - 098848 AU - Sachi Horibata AU - Edward J. Rice AU - Hui Zheng AU - Lynne J. Anguish AU - Chinatsu Mukai AU - Brooke A. Marks AU - Tinyi Chu AU - Scott A. Coonrod AU - Charles G. Danko Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/01/06/098848.abstract N2 - The molecular mechanisms of endocrine resistance in breast cancer remain poorly understood. Here we used PRO-seq to map the location of hundreds of genes and thousands of distal enhancers whose transcriptional activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen discovered increased transcription of the glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which we validate as both necessary and sufficient for resistance in MCF-7 cells. GDNF caused endocrine resistance by switching the active state of a bi-stable feedback loop in the MCF-7 regulatory network from ERα signaling to GDNF-RET signaling. To cause this switch, GDNF downregulated ERα transcription and activated the transcription factor EGR1, which, in turn, induced GDNF. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.HighlightsGDNF expression promotes endocrine resistance in MCF-7 cells.ER+ MCF-7 cells are poised for RET-mediated endocrine resistance, but lack expression of RET ligands.RET ligand expression predicts resistance to the aromatase inhibitor letrozole.GDNF regulatory network directly down-regulates ERα and indirectly up-regulates GDNF. ER -