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The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast CancerOrea-Soufi, Alba; email: firstname.lastname@example.org; Castillo-Lluva, Sonia; orcid: 0000-0001-5357-7178; email: email@example.com; Salvador-Tormo, Nélida; email: firstname.lastname@example.org; Martín-Cabrera, Paola; email: email@example.com; Recuero, Silvia; email: firstname.lastname@example.org; Gabicagogeascoa, Estíbaliz; email: email@example.com; Moreno-Valladares, Manuel; email: MANUEL.MORENOVALLADARES@osakidetza.eus; Mendiburu-Eliçabe, Marina; orcid: 0000-0003-2573-8709; email: firstname.lastname@example.org; Blanco-Gómez, Adrián; orcid: 0000-0002-1956-088X; email: email@example.com; Ramos-Pittol, José Miguel; orcid: 0000-0003-3753-5394; email: Jose.Ramos-Pittol@uibk.ac.at; et al. (MDPI, 2021-10-22)Background: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. Methods: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinformatic analyses in public datasets. Results: TRIB3 enhanced the proliferation and AKT phosphorylation in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. Conclusions: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer.