PLoS ONE (Jan 2018)

A bi-stable feedback loop between GDNF, EGR1, and ERα contribute to endocrine resistant breast cancer.

  • Sachi Horibata,
  • Edward J Rice,
  • Hui Zheng,
  • Chinatsu Mukai,
  • Tinyi Chu,
  • Brooke A Marks,
  • Scott A Coonrod,
  • Charles G Danko

DOI
https://doi.org/10.1371/journal.pone.0194522
Journal volume & issue
Vol. 13, no. 4
p. e0194522

Abstract

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Discovering regulatory interactions between genes that specify the behavioral properties of cells remains an important challenge. We used the dynamics of transcriptional changes resolved by PRO-seq to identify a regulatory network responsible for endocrine resistance in breast cancer. We show that GDNF leads to endocrine resistance by switching the active state in a bi-stable feedback loop between GDNF, EGR1, and the master transcription factor ERα. GDNF stimulates MAP kinase, activating the transcription factors SRF and AP-1. SRF initiates an immediate transcriptional response, activating EGR1 and suppressing ERα. Newly translated EGR1 protein activates endogenous GDNF, leading to constitutive GDNF and EGR1 up-regulation, and the sustained down-regulation of ERα. Endocrine resistant MCF-7 cells are constitutively in the GDNF-high/ ERα-low state, suggesting that the state in the bi-stable feedback loop may provide a 'memory' of endocrine resistance. Thus, we identified a regulatory network switch that contributes to drug resistance in breast cancer.