Triple-negative breast cancer (TNBC) is among the most aggressive forms of breast cancer with limited therapeutic options. TAK1 is implicated in aggressive behavior of TNBC, while means are not fully understood. Here, we report that pharmacological blockade of TAK1 signaling hampered ribosome biogenesis (RBG) by reducing expression of RBG regulators such as RRS1, while not changing expression of ribosomal core proteins. Importantly, TAK1 blockade upregulated expression of p53 target genes in cell lines carrying wild type (wt) TP53 but not in p53-mutant cells. By examining involvement of the ribosomal stress response, we found that p53 activation by blockade of TAK1 was prevented by depletion of ribosomal protein RPL11. Further, siRNA-mediated depletion of TAK1 or RELA resulted in activation of p53 signaling and this response was dependent on RPL11. Knockdown of RRS1 disrupted nucleolar organization and resulted in activation of p53. Genomic TCGA data showed that TNBCs express high levels of ribosome biogenesis regulators, and elevated RRS1 levels correlate with unfavorable prognosis. Cytotoxicity data showed that TNBC cell lines are more sensitive to TAK1 inhibitor compared to luminal and HER2+ cell lines. Together, the data indicate that TAK1 regulates p53 activation by controlling ribosome biogenesis factors, and the TAK1-ribosome axis is a potential therapeutic target in TNBC.

Citation Format: Andrei Bakin, Justin Zonneville. Tak1 signaling regulates p53 through a mechanism involving ribosomal stress [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-21.