Targeting TAZ-Driven Human Breast Cancer by Inhibiting a SKP2-p27 Signaling Axis

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Deregulated transcriptional coactivator WWTR1/TAZ (TAZ) is common in basal-like breast cancer (BLBC).
• The precise role of TAZ in breast cancer cell-cycle progression, proliferation, and tumor maintenance is not fully understood.

Purpose of the Study:

• To identify TAZ-dependent cellular programs critical for BLBC tumor growth and progression.
• To investigate the necessity of sustained TAZ expression for tumor genesis and maintenance.
• To elucidate the molecular mechanisms by which TAZ regulates cancer cell fate and identify downstream effectors.

Main Methods:

• Integrative oncogenomic approach to identify TAZ-dependent programs.
• In vivo studies involving temporal inhibition of TAZ to assess tumor growth and metastasis.
• Mechanistic investigations into TAZ-controlled gene profiles and cell-cycle networks.

Main Results:

• Sustained TAZ expression is essential for both the initiation and maintenance of BLBC tumors.
• Temporal inhibition of TAZ significantly reduced the burden of established pulmonary metastases.
• TAZ regulates distinct gene profiles impacting cell-cycle networks, with S-phase kinase-associated protein 2 (SKP2) playing a causal role in the neoplastic state.

Conclusions:

• TAZ is indispensable for BLBC tumor growth, maintenance, and metastasis.
• SKP2 acts as a key downstream effector of TAZ, mediating its oncogenic functions in BLBC.
• Targeting the TAZ-SKP2 axis offers a potential therapeutic strategy for TAZ-dependent breast cancers.