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Sporadic activation of an oxidative stress-dependent NRF2–p53 signaling network in breast epithelial spheroids and premalignancies

ABSTRACT: Breast–mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell-regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal 3D spheroids are cultured in basement membrane, and prior transcriptomic analyses identified a state associated with stress tolerance and poor response to anticancer therapeutics. Here, we examined the regulation of this state and found that it is jointly coordinated by the NRF2 and p53 pathways, which are co-stabilized by spontaneous oxidative stress within the 3D cultures. To identify common adaptive programs downstream of NRF2 deficiency, we inducibly knocked down NRF2 and profiled 3D spheroids by RNA sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141228 | GEO | 2020/02/04

REPOSITORIES: GEO

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