Abstract SY24-01: Translational rheostat that drives breast cancer metastasis

Abstract Dysregulation of mRNA translation plays a significant role in malignant transformation and neoplastic growth. The role of mRNA translation in metastasis is less well understood. Our findings suggest that translational repressor, 4E-binding protein 1 (4E-BP1), promotes metastatic spread. This is in contrast to its role in attenuating malignant transformation and primary tumor growth. Metastasis-promoting effects of 4E-BP1 are mediated by the selective perturbations in the translatome that bolster invasive capacity of breast cancer cells and their ability to overcome anoikis. We further demonstrate that 4E-BP1 activity is dynamically tuned in response to stressors acting during different steps in metastatic cascade which appears to be central from switching cancer cell phenotypes from proliferative to metastatic. Finally, the observed pro-metastatic effects appear to be specific to 4E-BP1, but not to its closely related paralogue 4E-BP2 which is further reflected by differential effect of these proteins on the translatome, and de novo synthesis of pro-metastatic proteins. Overall, our fundings suggest that 4E-BP1 is a central node of the translational rheostat that drives metastasis. Citation Format: Ivan Topisirovic. Translational rheostat that drives breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY24-01.