Abstract 3863: Targeting TACC3 inhibits metastasis in breast cancer with centrosome amplification

Abstract Centrosome amplification (CA) is highly prevalent in cancer. It is strongly associated with tumor progression and worse prognosis in a variety of different cancers. Preclinical studies have demonstrated that CA can trigger tumor initiation as well as cancer cell invasion. Thus, CA is known to be a promising therapeutic target. We have previously identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) as being overexpressed in tumors with CA. TACC3 forms distinct functional interactomes regulating spindle stability, clustering extra centrosomes and transcription of key tumor suppressors in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Despite the known mechanisms in tumor growth inhibition, the molecular mechanisms by which TACC3 drives tumor invasion and metastasis in cancers with CA remain underexplored. Here, we aim to test TACC3 targeting as a novel strategy to block invasion and metastasis and to elucidate the underlying mechanisms. We found that higher TACC3 levels are strongly associated with worse metastasis-free survival in breast cancer patients with CA. Using a combination of in vitro assays, transcriptomics, proximity labeling (APEX2-TACC3), and mass spectrometry, we demonstrate that TACC3 promotes cancer cell migration and invasion. In addition, we provide evidence that targeting TACC3 via a small-molecule inhibitor or CRISPR-Cas9-mediated knockout significantly reduces cell migration and invasion. Furthermore, TACC3 inhibition reduces the number of circulating tumor cells and spontaneous metastasis to the lungs in the MMTV-PyMT transgenic mouse model and lung-tropic breast cancer xenografts without any toxicity. Overall, our findings demonstrate the potential for TACC3 as a therapeutic target to inhibit metastasis in breast cancer with CA. This work offers new insights into the molecular underpinnings of TACC3’s role in metastatic breast cancer, particularly in CA-driven tumors and underscores its therapeutic relevance. Citation Format: Mustafa Emre Gedik, Ozge Saatci, Kubra Calisir, Metin Cetin, Burge Ulukan Altun, Ozlem Sener Sahin, Rony Hull, Lauren Ball, Elizabeth Hill, Chaemin Lim, Sridhar Vempati, Burcu Caliskan, Erden Banoglu, Ioulia Chatzistamou, Ozgur Sahin. Targeting TACC3 inhibits metastasis in breast cancer with centrosome amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3863.