GSE93229 RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ER α

Contributor : Charles G DankoSeries Type : OtherOrganism : Homo sapiensThe 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 activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen identified a 16-fold transcriptional increase in glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which is both necessary and sufficient for resistance in MCF-7 cells. GDNF causes endocrine resistance by switching the active state of a bi-stable feedback loop from ER α signaling to GDNF-RET signaling. To catalyze this switch, we found that GDNF directly downregulates ERα transcription and activates the transcription factor EGR1, which, in turn, induces GDNF expression. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance v ia the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research