Dataset Information

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

ABSTRACT: 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. 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. 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. Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer.

SUBMITTER: Orea-Soufi A

PROVIDER: S-EPMC8582533 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Orea-Soufi Alba A Castillo-Lluva Sonia S Salvador-Tormo Nélida N Martín-Cabrera Paola P Recuero Silvia S Gabicagogeascoa Estíbaliz E Moreno-Valladares Manuel M Mendiburu-Eliçabe Marina M Blanco-Gómez Adrián A Ramos-Pittol José Miguel JM García-Taboada Elena E Ocaña Alberto A Cimas Francisco J FJ Matheu Ander A Álvarez-López Isabel I Velasco Guillermo G Lorente Mar M

Cancers 20211022 21

<h4>Background</h4>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.<h4>Methods</h4>We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on ...[more]

PMID: 34771470

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Project description:BackgroundTribble pseudokinase 3 (TRIB3) plays a key role in regulating the malignancy of many tumors. This study examined its function in cancer cells and explored the potential mechanisms of action.MethodsThe expression of TRIB3 was examined in hepatocellular carcinomas (HCCs) using The Cancer Genome Atlas (TCGA) database. A TRIB3 lentivirus with a flag label was constructed and transfected into Huh7 and Hep3B human hepatoma cell lines to generate cells that stably overexpress TRIB3. A small interfering RNA (siRNA) was designed to knockdown TRIB3 mRNA in HepG2 and Huh7. Cell viability and cell colony formation assays were conducted. Flow cytometry was performed to assess the cell cycle in cells overexpressing TRIB3. Western blotting were performed to examine the expression of (Mitogen-activated protein kinase, MAPKK) (MEK), phosphorylated-MEK (p-MEK), extracellular signal-regulated kinase (ERK), and p-MEK in cells with TRIB3 knockdown. The correlation between TRIB3 and SMARCD3 was assessed using co-immunoprecipitation assays and immunofluorescence.ResultsTRIB3 was significantly overexpressed in advanced grade HCC tissues and was closely correlated with poor prognosis. TRIB3 overexpression promoted the cell growth and cell cycle but had little effect on migration capabilities in Huh7 and Hep3B cells. Conversely, knockdown of TRIB3 had slow down the cell growth in Huh7 and HepG2 cells detected by CCK8 and colony formation assay. The expression of MEK and ERK at both the protein and mRNA levels were downregulated when TRIB3 was knocked down. The protein expression of p-ERK and p-MEK were also downregulated upon TRIB3 silencing. SMARCD3 is a transcript factor that is belongs to the SWI/SNF complex and has been shown to regulate many genes. Indeed, co-immunoprecipitation assays demonstrated that TRIB3 interacts with SMARCD3 in the nucleus, suggesting that it may regulate TRIB3 in HCCs.ConclusionsThis study demonstrated that TRIB3 promotes the malignancy of HCC cells and its expression may be a potential diagnostic biomarker for HCC progression.

Project description:BackgroundOestrogen receptor (ER) positive (luminal) tumours account for the largest proportion of females with breast cancer. Theirs is a heterogeneous disease presenting clinical challenges in managing their treatment. Three main biological luminal groups have been identified but clinically these can be distilled into two prognostic groups in which Luminal A are accorded good prognosis and Luminal B correlate with poor prognosis. Further biomarkers are needed to attain classification consensus. Machine learning approaches like Artificial Neural Networks (ANNs) have been used for classification and identification of biomarkers in breast cancer using high throughput data. In this study, we have used an artificial neural network (ANN) approach to identify DACH1 as a candidate luminal marker and its role in predicting clinical outcome in breast cancer is assessed.Materials and methodsA reiterative ANN approach incorporating a network inferencing algorithm was used to identify ER-associated biomarkers in a publically available cDNA microarray dataset. DACH1 was identified in having a strong influence on ER associated markers and a positive association with ER. Its clinical relevance in predicting breast cancer specific survival was investigated by statistically assessing protein expression levels after immunohistochemistry in a series of unselected breast cancers, formatted as a tissue microarray.ResultsStrong nuclear DACH1 staining is more prevalent in tubular and lobular breast cancer. Its expression correlated with ER-alpha positive tumours expressing PgR, epithelial cytokeratins (CK)18/19 and 'luminal-like' markers of good prognosis including FOXA1 and RERG (p<0.05). DACH1 is increased in patients showing longer cancer specific survival and disease free interval and reduced metastasis formation (p<0.001). Nuclear DACH1 showed a negative association with markers of aggressive growth and poor prognosis.ConclusionNuclear DACH1 expression appears to be a Luminal A biomarker predictive of good prognosis, but is not independent of clinical stage, tumour size, NPI status or systemic therapy.

Dataset Information

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

Publications

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

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