Abstract PS1-13-21: Multi-layered Inhibition of Metastasis by Targeting TACC3 in Breast Cancer with Centrosome Amplification

Abstract Metastasis is the primary cause of cancer-associated mortality, accounting for about 90% of cancer deaths. Cell migration is the pivotal step in metastasis that enables cancer cells disseminate out of a primary tumor to distant organs. Cell polarization is a fundamental cellular process, allowing cancer cells gain directionality that is critical for migration. Centrosomes direct cell polarity via promoting microtubule assembly and elongation. However, little is known about the molecular mechanisms and drivers of cancer cell polarity which would ultimately provide therapeutic targets to inhibit the deadly metastasis. Here, we found that the mutifunctional adaptor protein TACC3 promotes cell polarity, migration, and invasion in breast cancer cells with amplified centrosomes (CA). We showed that higher TACC3 levels are strongly associated with worse metastasis-free survival in breast cancer patients with CA. By integrating transcriptomics, proximity labeling (APEX2-TACC3) coupled to mass spectrometry, siRNA screening, and functional assays, we demonstrated that TACC3 promotes cancer cell migration and invasion by multilayered regulation of microtubule assembly, actin cytoskeleton, and vesicle trafficking. In addition, we provide evidence that targeting TACC3 via a first-in-class clinically tested 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 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: O. Saatci, M. Gedik, K. Calisir, B. Cerci, B. Ulukan Altun, O. Sener Sahin, R. Hull, L. Ball, E. Hill, C. Lim, S. Vempati, B. Caliskan, E. Banoglu, I. Chatzistamou, O. Sahin. Multi-layered Inhibition of Metastasis by Targeting TACC3 in Breast Cancer with Centrosome Amplification [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-13-21.