Abstract C120: TACC3 is a driver of metastasis in centrosome-amplified breast cancer

Abstract Centrosome amplification (CA) is a hallmark of aggressive cancers, strongly linked to tumor progression, invasion, and poor clinical outcomes. While preclinical studies suggest CA plays a direct role in tumor initiation and metastatic spread, therapeutic strategies targeting CA remain limited. We previously identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) as a key regulator overexpressed in CA-positive tumors. TACC3 governs spindle integrity, clusters supernumerary centrosomes, and modulates transcriptional programs critical for the survival of CA-bearing cancer cells. However, the molecular mechanisms by which TACC3 drives invasion and metastasis remain largely unknown. In this study, we uncover TACC3 as a central mediator of metastatic progression in breast cancers with CA. Clinically, elevated TACC3 expression correlates with significantly worse metastasis-free survival in patients harboring CA-positive tumors. Functionally, using in vitro assays, transcriptomics, proximity labeling (APEX2-TACC3), and mass spectrometry, we show that TACC3 orchestrates cancer cell migration and invasion through novel interactions with cytoskeletal, vesicle trafficking, and leading-edge proteins. Importantly, pharmacologic inhibition with AO252, clinical grade TACC3 inhibitor or CRISPR-Cas9–mediated knockout of TACC3 disrupts these interactions and significantly impairs invasive behavior. In vivo, TACC3 inhibition markedly suppresses local invasion, circulating tumor cells, and spontaneous lung metastasis in both MMTV-PyMT transgenic mice and lung-tropic breast cancer xenografts, without inducing systemic toxicity. Together, our findings establish TACC3 as a druggable driver of metastasis in centrosome-amplified breast cancer and offer new mechanistic insights. This work highlights a novel therapeutic strategy for halting metastasis in a highly aggressive breast cancer subtype. Citation Format: Ozge Saatci, Kubra Calisir Unsal, Baris Cerci, Mustafa Emre. Gedik, Metin Cetin, Ozlem Sener Sahin, Rony Hull, Lauren Ball, Elizabeth Hill, Ioulia Chatzistamou, Chaemin Lim, Sridhar Vempati, Burcu Caliskan, Erden Banoglu, Ozgur Sahin. TACC3 is a driver of metastasis in centrosome-amplified breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C120.