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Simple Summary: Breast cancer is the most frequent type of cancer in women. More than 70% of these tumors belong to the so-called luminal subtype which has, in general, a good prognosis. However, a fraction of patients with luminal breast cancer progress to an advanced or metastatic disease, which remains a major clinical and social problem. Therefore, it is crucial to identify novel biomarkers that help to predict the progression of the disease and to develop more efficacious therapeutic approaches to fight advanced luminal breast cancer. In this work we found that the increased expression of the protein tribbles pseudokinase 3 (TRIB3) is associated with a good prognosis and a better response to therapy in luminal breast cancer patients. We also found that this effect is at least in part due to the ability of TRIB3 to inhibit the activity of the oncogene HER2. 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. [ABSTRACT FROM AUTHOR]