Targeting the UFL1-AKT cascade suppresses triple-negative breast cancer progression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
• The role of UFL1-mediated UFMylation in TNBC pathogenesis is not well understood.
• AKT signaling is frequently dysregulated in TNBC.

Purpose of the Study:

• To investigate the role of UFL1-mediated UFMylation in TNBC.
• To elucidate the interaction between UFL1 and AKT1 in TNBC.
• To evaluate the therapeutic potential of targeting the UFL1-AKT axis.

Main Methods:

• Co-immunoprecipitation to assess UFL1-AKT1 interaction.
• Western blotting to detect UFMylation and phosphorylation.
• In vitro and in vivo TNBC models to evaluate PDAU-TAT efficacy.
• Analysis of clinical TNBC specimens for UFL1 and AKT activation markers.

Main Results:

• AKT1 interacts with UFL1 and is UFMylated at specific lysine residues, enhancing its activation.
• UFMylation of AKT1 promotes TNBC tumor growth and chemoresistance.
• AKT1 phosphorylates UFL1, creating a positive feedback loop sustaining their oncogenic activity.
• Disruption of the UFL1-AKT interaction via PDAU-TAT inhibits TNBC progression.
• Elevated pT426 UFL1 correlates with high pAKT in clinical TNBC samples.

Conclusions:

• A UFL1-AKT positive feedback loop is critical for TNBC progression.
• Targeting this UFL1-AKT axis represents a promising therapeutic strategy for TNBC.
• This approach may also benefit other aggressive cancers with UFL1 and AKT activation.