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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Triple-negative breast cancer (TNBC) is aggressive and heterogeneous, necessitating subtype-specific therapeutic strategies.
• TNBC cells depend on exogenous cystine via SLC7A11/xCT for glutathione synthesis and oxidative stress response.
• Mesenchymal stem-like (MSL) TNBC subtype exhibits unique vulnerabilities and resistance mechanisms.

Purpose of the Study:

• To elucidate the molecular mechanisms of oxidative stress defense in MSL TNBC.
• To identify novel therapeutic targets for MSL TNBC based on subtype-specific vulnerabilities.
• To investigate the role of the cystine/glutamate antiporter and NRF2 pathway in MSL TNBC progression.

Main Methods:

• Analysis of TNBC cell lines, focusing on the MSL subtype.
• Investigation of cystine uptake, NRF2 activation, and KEAP1 modification.
• Gene expression profiling and survival analysis of key upregulated genes.
• Functional studies involving exogenous gene expression to assess cell survival.

Main Results:

• MSL TNBC cells activate NRF2 through direct KEAP1 cysteinylation, independent of glutathione.
• Cystine-driven NRF2 activation promotes oxidative stress response, epithelial-to-mesenchymal transition, and stem-like phenotypes.
• Upregulated genes OSGIN1, RGS17, SRXN1, and AKR1B10 are identified as negative prognostic markers for TNBC.
• Exogenous OSGIN1 or NRF2 expression protects MSL TNBC cells from cystine depletion-induced death.

Conclusions:

• The cystine/NRF2/OSGIN1 axis is crucial for MSL TNBC survival and phenotype maintenance.
• This axis represents a promising therapeutic target for treating aggressive MSL TNBC.
• Understanding subtype-specific metabolic dependencies is key to developing effective TNBC therapies.