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Updated: Aug 8, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification
Ozge Saatci1,2, Ozge Akbulut1, Metin Cetin1,2
1Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, USA.
Abstract:
Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease.
Insights
Transforming acidic coiled-coil containing protein 3 (TACC3) drives aggressive cancers with centrosome amplification. Inhibiting TACC3 halts cancer growth by disrupting mitosis and cell cycle progression, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Centrosome amplification (CA) is a hallmark of aggressive cancers, yet its molecular drivers and regulation beyond mitosis remain unclear.
- Extra centrosomes in cancer cells necessitate clustering for mitotic fidelity, preventing cell death.
- Understanding the mechanisms of cancer aggressiveness linked to CA is crucial for developing targeted therapies.
Purpose of the Study:
- To identify molecular players overexpressed in tumors with CA and associated with poor clinical outcomes.
- To elucidate the distinct roles of TACC3 in mitosis and interphase of cancer cells with CA.
- To evaluate TACC3 as a therapeutic target for aggressive breast cancers with CA.
Main Methods:
- Overexpression analysis of TACC3 in tumors with CA.
- Co-immunoprecipitation and functional assays to identify TACC3 interactomes (KIFC1, NuRD complex).
- In vitro and in vivo studies using organoids and xenografts with TACC3 inhibition (siRNA, small molecule inhibitors).
Main Results:
- TACC3 is overexpressed in CA-positive tumors, correlating with worse patient outcomes.
- Mitotic TACC3-KIFC1 interaction clusters supernumerary centrosomes; its inhibition causes mitotic catastrophe.
- Interphase TACC3-NuRD interaction suppresses tumor suppressors (p21, p16, APAF1), promoting cell cycle progression; inhibition induces G1 arrest and apoptosis.
- Targeting TACC3 significantly inhibits tumor growth in preclinical models of breast cancer with CA.
Conclusions:
- TACC3 is a multifunctional protein essential for the proliferation and survival of cancer cells with CA.
- TACC3 orchestrates both mitotic progression (via KIFC1) and cell cycle advancement (via NuRD) in CA-driven cancers.
- Targeting TACC3 represents a promising therapeutic strategy for aggressive breast cancers characterized by centrosome amplification.
