The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-19, pub-electronic 2021-10-22Publication status: PublishedFunder: Instituto de Salud Carlos III; Grant(s): PI18/00442Funder: European Commission; Grant(s): ITN-308 2016 721532Funder: Breast Cancer Now; Grant(s): 2012NovSP033Funder: Ministry of Economy, Industry and Competitiveness; Grant(s): RTI2018-094130-B-100Background: 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

Papel de la pseudoquinasa Tribbles 3 en cáncer de mama: estudios mecanísticos e implicaciones en el pronóstico del subtipo lumina

El cáncer de mama es el tipo tumoral más frecuente en mujeres. Numerosos estudios sobre los procesos moleculares implicados en el desarrollo tumoral mamario han incrementado el conocimiento de esta patología y han permitido la identificación de biomarcadores pronósticos y el desarrollo de nuevas terapias. Sin embargo, sigue siendo la principal causa de muerte por cáncer en mujeres en la mayoría de los países. Se trata de una patología muy heterogénea que se clasifica atendiendo a distintos marcadores moleculares, siendo el subtipo tumoral más frecuente el cáncer de mama luminal, caracterizado por la expresión del receptor de estrógenos y diversas citoqueratinas características de las células epiteliales luminales que conforman los ductos mamarios. TRIB3 es una pseudoquinasa que pertenece a la familia de las proteínas Tribbles y cuya desregulación se ha visto implicada en el desarrollo de distintas patologías, entre las que destacan los trastornos cardiovasculares y el cáncer. Concretamente en cáncer, se ha propuesto que TRIB3 puede desempeñar una acción pro- o antitumoral según el contexto celular y tipo de tumor y, particularmente en cáncer de mama, la bibliografía existente es escasa y poco concluyente..

FOXO transcription factors as therapeutic targets in human diseases

Forkhead box (FOX)O proteins are transcription factors (TFs) with four members in mammals designated FOXO1, FOXO3, FOXO4, and FOXO6. FOXO TFs play a pivotal role in the cellular adaptation to diverse stress conditions. FOXO proteins act as context-dependent tumor suppressors and their dysregulation has been implicated in several age-related diseases. FOXO3 has been established as a major gene for human longevity. Accordingly, FOXO proteins have emerged as potential targets for the therapeutic development of drugs and geroprotectors. In this review, we provide an overview of the most recent advances in our under-standing of FOXO regulation and function in various pathological conditions. We discuss strategies targeting FOXOs directly or by the modulation of upstream regulators, shedding light on the most promising intervention points. We also reveal the most relevant clinical indications and discuss the potential, trends, and challenges of modulating FOXO activity for therapeutic purposes.info:eu-repo/semantics/publishedVersio

Phosphorylation of FOXO Proteins as a Key Mechanism to Regulate Their Activity

Phosphorylation of FOXO transcription factors is one of the key mechanisms involved in the regulation of the activity, nucleo-cytosolic shuttling, and stability of this family of proteins. Here, we describe several experimental approaches allowing analysis of changes in the phosphorylation of these proteins upon exposure to different stimuli

TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells

Aberrant expression or activity of proteins are amongst the best understood mechanisms that can drive cancer initiation and progression, as well as therapy resistance. TRIB3, a member of the Tribbles family of pseudokinases, is often dysregulated in cancer and has been associated with breast cancer initiation and metastasis formation. However, the underlying mechanisms by which TRIB3 contributes to these events are unclear. In this study, we demonstrate that TRIB3 regulates the expression of PPARγ, a transcription factor that has gained attention as a potential drug target in breast cancer for its antiproliferative actions. Proteomics and phosphoproteomics analyses together with classical biochemical assays indicate that TRIB3 interferes with the MLL complex and reduces MLL-mediated H3K4 trimethylation of the PPARG locus, thereby reducing PPARγ mRNA expression. Consequently, the overexpression of TRIB3 blunts the antiproliferative effect of PPARγ ligands in breast cancer cells, while reduced TRIB3 expression gives the opposite effect. In conclusion, our data implicate TRIB3 in epigenetic gene regulation and suggest that expression levels of this pseudokinase may serve as a predictor of successful experimental treatments with PPARγ ligands in breast cancer

The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

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