Genomics

Dataset Information

100

RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ERα


ABSTRACT: 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 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 ERα 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 via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands. Overall design: PRO-seq was used to analyze four different MCF-7 cell subclones in seven different biological conditions.

INSTRUMENT(S): Illumina NextSeq 500 (Homo sapiens)

SUBMITTER: Charles G Danko  

PROVIDER: GSE93229 | GEO | 2018-02-22

REPOSITORIES: GEO

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Publications

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

Horibata Sachi S   Rice Edward J EJ   Mukai Chinatsu C   Marks Brooke A BA   Sams Kelly K   Zheng Hui H   Anguish Lynne J LJ   Coonrod Scott A SA   Danko Charles G CG  

PloS one 20180402 4


The RET tyrosine kinase signaling pathway is involved in the development of endocrine resistant ER+ breast cancer. However, we know little about how ER+ cells activate RET signaling and initiate an endocrine resistant phenotype. Here we show that both ER+ endocrine resistant and sensitive breast cancers have a 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 R  ...[more]

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