NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.

Journal Article (Journal Article)

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.

Full Text

Duke Authors

Cited Authors

  • Fox, DB; Garcia, NMG; McKinney, BJ; Lupo, R; Noteware, LC; Newcomb, R; Liu, J; Locasale, JW; Hirschey, MD; Alvarez, JV

Published Date

  • April 2020

Published In

Volume / Issue

  • 2 / 4

Start / End Page

  • 318 - 334

PubMed ID

  • 32691018

Pubmed Central ID

  • PMC7370851

Electronic International Standard Serial Number (EISSN)

  • 2522-5812

Digital Object Identifier (DOI)

  • 10.1038/s42255-020-0191-z

Language

  • eng

Conference Location

  • Germany