Autophagy-targeted NBR1-p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Autophagy plays a crucial role in cellular proteostasis and is implicated in cancer progression.
• Defects in autophagy are increasingly recognized as drivers of cancer metastasis.
• The cargo receptors NBR1 and p62/SQSTM1 are key components of the autophagy pathway.

Purpose of the Study:

• To elucidate the role of autophagy deficiency in breast cancer metastasis.
• To investigate the mechanism by which NBR1 and p62/SQSTM1 accumulation promotes metastasis.
• To identify therapeutic targets for inhibiting autophagy-driven breast cancer progression.

Main Methods:

• Utilized mouse and human breast cancer models.
• Investigated the formation of NBR1-p62/SQSTM1 biomolecular condensates.
• Assessed the interaction between NBR1-p62/SQSTM1 complexes, ITCH, and p63.
• Studied the impact of mutant NBR1 on metastasis in vivo.

Main Results:

• Autophagy deficiency leads to the accumulation of NBR1 and p62/SQSTM1 cargo receptors in breast cancer cells.
• Accumulated NBR1-p62/SQSTM1 complexes sequester the ubiquitin ligase ITCH, stabilizing the pro-metastatic factor p63.
• This stabilization of p63 drives basal differentiation and promotes metastasis in both mouse and human models.
• Mutant NBR1 that cannot sequester ITCH abrogates these pro-metastatic effects.

Conclusions:

• Autophagy suppression in breast cancer promotes metastasis via NBR1-p62/SQSTM1 complex formation and p63 stabilization.
• Therapeutic inhibition of autophagy can lead to proteostatic defects that enhance breast cancer's metastatic potential.
• Targeting these NBR1-p62/SQSTM1-ITCH-p63 axis interactions may offer novel therapeutic strategies for breast cancer.