Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous group of tumors, and there is an urgent need to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy in order to develop effective therapeutic strategies. A subgroup of TNBC cells overexpresses the cystine/glutamate antiporter SLC7A11/xCT, which makes them highly dependent on exogenous cystine to fuel glutathione synthesis and promote an oxidative stress response to sustain their high metabolic demands. With this work, we demonstrate that TNBC cells of the mesenchymal stem-like (MSL) subtype utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to protect against oxidative stress. Mechanistically, we prove that cysteine-mediated NRF2 activation occurs by direct cysteinylation of the repressor KEAP1. Furthermore, we show that the interaction induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Of note, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, both exogenous expression of NRF2 and OSGIN1 can prevent cell death of MSL TNBC cells by cysteine deprivation. The results suggest that the cystine/NRF2/OSGIN1 axis may represent a potential target for effective treatment of MSL TNBCs.

NRF2 activation by cysteine as a survival mechanism in triple-negative breast cancer

BOTTONI, LAURA
2025

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous group of tumors, and there is an urgent need to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy in order to develop effective therapeutic strategies. A subgroup of TNBC cells overexpresses the cystine/glutamate antiporter SLC7A11/xCT, which makes them highly dependent on exogenous cystine to fuel glutathione synthesis and promote an oxidative stress response to sustain their high metabolic demands. With this work, we demonstrate that TNBC cells of the mesenchymal stem-like (MSL) subtype utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to protect against oxidative stress. Mechanistically, we prove that cysteine-mediated NRF2 activation occurs by direct cysteinylation of the repressor KEAP1. Furthermore, we show that the interaction induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Of note, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, both exogenous expression of NRF2 and OSGIN1 can prevent cell death of MSL TNBC cells by cysteine deprivation. The results suggest that the cystine/NRF2/OSGIN1 axis may represent a potential target for effective treatment of MSL TNBCs.
10-apr-2025
Inglese
GALVAGNI, FEDERICO
Università degli Studi di Siena
Siena
85
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14242/201595
Il codice NBN di questa tesi è URN:NBN:IT:UNISI-201595