Comparison of SYK Signaling Networks Reveals the Potential Molecular Determinants of Its Tumor-Promoting and Suppressing Functions

Spleen tyrosine kinase (SYK) can behave as an oncogene or a tumor suppressor, depending on the cell and tissue type. As pharmacological SYK inhibitors are currently evaluated in clinical trials, it is important to gain more information on the molecular mechanisms underpinning these opposite roles. To this aim, we reconstructed and compared its signaling networks using phosphoproteomic data from breast cancer and Burkitt lymphoma cell lines where SYK behaves as a tumor suppressor and promoter. Bioinformatic analyses allowed for unveiling the main differences in signaling pathways, network topology and signal propagation from SYK to its potential effectors. In breast cancer cells, the SYK target-enriched signaling pathways included intercellular adhesion and Hippo signaling components that are often linked to tumor suppression. In Burkitt lymphoma cells, the SYK target-enriched signaling pathways included molecules that could play a role in SYK pro-oncogenic function in B-cell lymphomas. Several protein interactions were profoundly rewired in the breast cancer network compared with the Burkitt lymphoma network. These data demonstrate that proteomic profiling combined with mathematical network modeling allows untangling complex pathway interplays and revealing difficult to discern interactions among the SYK pathways that positively and negatively affect tumor formation and progression.

Download Full-text

Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.608044 ◽

2021 ◽

Vol 8 ◽

Author(s):

Stefanie Chan ◽

Emma Smith ◽

Yuan Gao ◽

Julian Kwan ◽

Benjamin C. Blum ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Tumor Growth ◽

G Protein ◽

Molecular Mechanisms ◽

Akt Signaling ◽

Proteomic Profiling ◽

Potential Biomarker ◽

Regulated Gene Expression

G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.

Download Full-text

Molecular Mechanisms Underlying the Anti-Breast Cancer Stem Cell Activity of Pterocladia capillacea and Corallina officinalis Polysaccharides

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210727122756 ◽

2021 ◽

Vol 21 ◽

Author(s):

Hebatallah G. Hafez ◽

Rafat M. Mohareb ◽

Sohair M. Salem ◽

Azza A. Matloub ◽

Emad F. Eskander ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Protein Complexes ◽

Cell Activity ◽

Sulfated Polysaccharide ◽

Corallina Officinalis ◽

Stem Cell Activity ◽

Mcf 7

Objective: This study aimed to appraise the activity of Pterocladia capillacea and Corallina officinalis polysaccharides against breast cancer stem cells (BCSCs). P. capillacea and C. officinalis polysaccharides were characterized to be sulfated polysaccharide-protein complexes. Methods: Cytotoxicity of the polysaccharides against MDA-MB-231 and MCF-7 cell lines along with their impact on CD44+/CD24− and aldehyde dehydrogenase 1(ALDH1) positive BCSC population were determined. Their effect on gene expression of CSC markers, Wnt/β-catenin and Notch signaling pathways was evaluated. Results: P. capillacea and C. officinalis polysaccharides inhibited the growth of breast cancer cells and reduced BCSC subpopulation. P. capillacea polysaccharides significantly down-regulated OCT4, SOX2, ALDH1A3 and vimentin in MDA-MB-231 as well as in MCF-7 cells except for vimentin that was up-regulated in MCF-7 cells. C. officinalis polysaccharides exhibited similar effects except for OCT4 that was up-regulated in MDA-MB-231 cells. Significant suppression of Cyclin D1 gene expression was noted in MDA-MB-231 and MCF-7 cells treated with P. capillacea or C. officinalis polysaccharides. β-catenin and c-Myc genes were significantly down-regulated in MDA-MB-231 cells treated with C. officinalis and P. capillacea polysaccharides, respectively, while being up-regulated in MCF-7 cells treated with either of them. Additionally, P. capillacea and C. officinalis polysaccharides significantly down-regulated Hes1 gene in MCF-7 cells despite increasing Notch1 gene expression level. However, significant down-regulation of Notch1 gene was observed in MDA-MB-231 cells treated with P. capillacea polysaccharides. Conclusion: Collectively, this study provides evidence for the effectiveness of P. capillacea and C. officinalis polysaccharides in targeting BCSCs through interfering with substantial signaling pathways contributing to their functionality.

Download Full-text

Tumor suppressor microRNAs: Targeted molecules and signaling pathways in breast cancer

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2016.04.011 ◽

2016 ◽

Vol 81 ◽

pp. 305-317 ◽

Cited By ~ 16

Author(s):

F. Asghari ◽

N. Haghnavaz ◽

B. Baradaran ◽

M. Hemmatzadeh ◽

T. Kazemi

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Signaling Pathways

Download Full-text

FBLN5 Is an Underlying Common Tumor Suppressor in Breast Cancer and Thyroid Cancer

10.21203/rs.3.rs-1162202/v1 ◽

2022 ◽

Author(s):

Zhao-min XIE ◽

Ying-sheng XIAO ◽

Chun-yan XU ◽

Qin XIE ◽

Wen-de WANG ◽

...

Keyword(s):

Breast Cancer ◽

Thyroid Cancer ◽

Tumor Suppressor ◽

Molecular Mechanisms ◽

Differential Expression Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Gene ◽

Hormone Biosynthesis ◽

Key Genes

Abstract Background: Breast cancer (BC) patients have a greater risk of developing thyroid cancer (TC) than the general population. Similarly, TC patients are more likely to develop BC, suggesting an underlying common etiology. In this study, we sought to identify the potential cross-talking pathway and related molecular mechanisms conferring to the sequential development of BC and TC.Methods: We first used Multiple Primary-Standardized Incidence Ratios (MP-SIR) Program of SEER*Stat to calculate SIR to confirm the relationship between BC and TC. Then the RNA-seq was downloaded from The Cancer Genome Atlas (TCGA). And we built a co-expression network via Weighted Gene Co-expression Network Analysis (WGCNA) and obtained the most significant modules. The key genes were obtained by differential gene expression (DGE) analysis and WGCNA analysis. Furthermore, String database and Cytoscape software were used to construct protein-protein interactions (PPI), and defined the maximum Maximal Clique Centrality (MCC) value as hub gene.Then we performed prognosis analysis on the hub genes and obtained the prognostic genes of BC and TC. Finally, gene set enrichment analysis (GSEA) was used to investigate the molecular pathways associated with prognostic gene expressed both in BC and TC.Results: From the SEER database, we found that the risk of developing BC in TC patients was SIR 1.12, 95% CI [1.07, 1.18], and the risk of developing BC in TC patients was SIR 1.29, 95% CI [1.23, 1.26]. Fifty-nine key genes obtained by differential expression analysis and WGCNA identify that PI3K/AKT was the most enriched pathway in BC and TC. In addition, the Recombinant Fibulin 5 (FBLN5) was shown to be of significant prognostic value for both BC and TC and was down-regulated in BC and TC tissues. GSEA demonstrated that FBLN5 enrichment pathways associated with BC and TC mainly included: B cell receptor signaling pathway, steroid hormone biosynthesis, and pathways in cancer.Conclusions: The PI3K/AKT signaling is most co-enriched pathway in BC and TC. FBLN5 is the most relevant prognostic gene and an underlying common tumor suppressor in both BC and TC, with down-stream pathways involving immunity, hormone biosynthesis and carcinogenesis.

Download Full-text

PD-L1 Blockade by Atezolizumab Downregulates Signaling Pathways Associated with Tumor Growth, Metastasis, and Hypoxia in Human Triple Negative Breast Cancer

Cancers ◽

10.3390/cancers11081050 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1050 ◽

Cited By ~ 12

Author(s):

Reem Saleh ◽

Rowaida Z. Taha ◽

Varun Sasidharan Nair ◽

Nehad M. Alajez ◽

Eyad Elkord

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Signaling Pathways ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Cancer Therapies ◽

Rna Seq ◽

Mesenchymal Transition

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, which shows resistance to common breast cancer therapies, as it lacks the expression of the most common breast cancer targets. Therefore, TNBC treatment remains a challenge. Targeting programmed cell death-ligand 1 (PD-L1) by monoclonal antibodies (mAbs), for example, atezolizumab, has revolutionized the treatment for various cancer types. However, the therapeutic efficacy of targeting PD-L1 in TNBC is currently under investigation. In this study, we investigated the molecular mechanisms by which the human TNBC cell line MDA-MB-231, expressing PD-L1, responds to atezolizumab, using RNA-Seq. Transcriptome analysis revealed 388 upregulated and 362 downregulated genes in response to atezolizumab treatment. The expression of selected genes, from RNA-Seq data, was subsequently validated using RT-qPCR in the MDA-MB-231 and MDA-MB-468 TNBC cells following atezolizumab treatment. Bioinformatics analysis revealed that atezolizumab downregulates genes promoting cell migration/invasion and metastasis, epithelial-mesenchymal transition (EMT), cell growth/proliferation/survival, and hypoxia. On the contrary, genes associated with apoptosis and DNA repair were upregulated in response to atezolizumab treatment. Gene set enrichment analyses revealed that a significant number of these genes are related to the NF-kB, PI3K/Akt/mTOR, MAPK, and CD40 signaling pathways. Using functional assays, we confirmed that atezolizumab increases MDA-MB-231 cell apoptosis/necrosis, and reduces their proliferation and viability. Collectively, our findings provide novel insights into the molecular mechanisms/signaling pathways by which atezolizumab exerts inhibitory effects on TNBC, thereby inhibiting EMT/metastasis, tumor growth/survival, and the induction of hypoxia.

Download Full-text

ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147

10.1101/338244 ◽

2018 ◽

Author(s):

Defang Zhou ◽

Jingwen Xue ◽

Pingping Zhuang ◽

Xiyao Cui ◽

Shuhai He ◽

...

Keyword(s):

Tumor Suppressor ◽

Molecular Mechanism ◽

Tumor Suppressor Genes ◽

Large Scale ◽

Molecular Mechanisms ◽

Tumor Formation ◽

Signalling Pathway ◽

Suppressor Genes ◽

Pathway Crosstalk ◽

Pathogenic Effects

AbstractThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV), as two oncogenic retroviruses, showed synergistic pathogenic effects characterized by enhanced tumor initiation and progression. The molecular mechanism underlying synergistic effects of ALV-J and REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and REV enhanced the ability of virus infection, increased viral life cycle, maintained cell survival and enhanced tumor formation. We combined the high-throughput proteomic readout with a large-scale miRNA screening to identify which molecules are involved in the synergism. Our results revealed co-infection of ALV-J and REV activated a latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. Our results contributed to the understanding of the molecular mechanisms of viral synergistic tumorgenesis, which provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes.Author summaryThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection with ALV-J and REV showed synergistic pathogenic effects characterized by enhanced tumor progression, however, the molecular mechanism on the neoplasia remains unclear. Our results revealed co-infection of ALV-J and REV promotes tumorigenesis by both induction of a latent oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-147. Mechanistic studies revealed that ALV-J and REV synergistically enhance KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. These results provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes, indicating the potential preventive target and predictive factor for ALV-J and REV induced tumorigenesis.

Download Full-text

Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

International Journal of Breast Cancer ◽

10.4061/2011/352182 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 45

Author(s):

Gabriel L. Fiszman ◽

María A. Jasnis

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Breast Cancers ◽

Trastuzumab Resistance ◽

Alternative Pathways ◽

Downstream Signaling ◽

Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

Download Full-text

Negative Cross Talk between NFAT1 and Stat5 Signaling in Breast Cancer

Molecular Endocrinology ◽

10.1210/me.2011-1141 ◽

2011 ◽

Vol 25 (12) ◽

pp. 2054-2064 ◽

Cited By ~ 15

Author(s):

Jiamao Zheng ◽

Feng Fang ◽

Xianke Zeng ◽

Terry R. Medler ◽

Alyson A. Fiorillo ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Progression ◽

Cross Talk ◽

Molecular Mechanisms ◽

Inhibitory Effect ◽

Tumor Formation ◽

Signaling Cascades ◽

Activated T Cells ◽

Downstream Target

Abstract The molecular mechanisms that modulate the activity of the signal transducers and activators of transcription 5 (Stat5) during the progression of breast cancer remain elusive. Here, we present evidence that the calcineurin/nuclear factor of activated T cells (NFAT) pathway negatively regulates the activation of Stat5, and vice versa in breast cancer. NFAT1 interacts with Stat5 in breast cancer cells, and their physical association is mediated by the DNA binding and transactivation domains of Stat5. Ectopically expressed NFAT1 is capable of inhibiting Stat5-dependent functions, including Stat5 transactivation, Stat5-mediated transcription of the downstream target gene expression, and binding of Stat5a to the Stat5 target promoter. By contrast, overexpression of a selective NFAT inhibitor VIVIT reversed NFAT1-mediated suppression of Stat5-dependent gene expression, whereas silencing of NFAT1 through RNA interference enhanced prolactin-induced, Stat5-mediated gene transcription, and breast cancer cell proliferation. A reciprocal inhibitory effect of Stat5 activity on NFAT1 signaling was also observed, implying these two signaling cascades antagonize each other in breast cancer. Importantly, analysis of a matched breast cancer progression tissue microarray revealed a negative correlation between levels of NFAT1 and Stat5 (pY694) during the progression of breast cancer. Taken together, these studies highlight a novel negative cross talk between the NFAT1- and Stat5-signaling cascades that may affect breast tumor formation, growth, and metastasis.

Download Full-text

Systems Medicine Design for Triple-Negative Breast Cancer and Non-Triple-Negative Breast Cancer Based on Systems Identification and Carcinogenic Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms22063083 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3083

Author(s):

Shan-Ju Yeh ◽

Bo-Jie Hsu ◽

Bor-Sen Chen

Keyword(s):

Breast Cancer ◽

Systems Biology ◽

Signaling Pathways ◽

Triple Negative Breast Cancer ◽

Molecular Mechanisms ◽

Triple Negative ◽

Potential Candidate ◽

Systems Medicine ◽

Mesenchymal Transition ◽

Systematic Procedure

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancers with poor prognosis. The etiology of triple-negative breast cancer (TNBC) is involved in various biological signal cascades and multifactorial aberrations of genetic, epigenetic and microenvironment. New therapeutic for TNBC is urgently needed because surgery and chemotherapy are the only available modalities nowadays. A better understanding of the molecular mechanisms would be a great challenge because they are triggered by cascade signaling pathways, genetic and epigenetic regulations, and drug–target interactions. This would allow the design of multi-molecule drugs for the TNBC and non-TNBC. In this study, in terms of systems biology approaches, we proposed a systematic procedure for systems medicine design toward TNBC and non-TNBC. For systems biology approaches, we constructed a candidate genome-wide genetic and epigenetic network (GWGEN) by big databases mining and identified real GWGENs of TNBC and non-TNBC assisting with corresponding microarray data by system identification and model order selection methods. After that, we applied the principal network projection (PNP) approach to obtain the core signaling pathways denoted by KEGG pathway of TNBC and non-TNBC. Comparing core signaling pathways of TNBC and non-TNBC, essential carcinogenic biomarkers resulting in multiple cellular dysfunctions including cell proliferation, autophagy, immune response, apoptosis, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), and cell differentiation could be found. In order to propose potential candidate drugs for the selected biomarkers, we designed filters considering toxicity and regulation ability. With the proposed systematic procedure, we not only shed a light on the differences between carcinogenetic molecular mechanisms of TNBC and non-TNBC but also efficiently proposed candidate multi-molecule drugs including resveratrol, sirolimus, and prednisolone for TNBC and resveratrol, sirolimus, carbamazepine, and verapamil for non-TNBC.

Download Full-text

Rab 25: Oncogenes and Tumor Suppressive of Cancer

E3S Web of Conferences ◽

10.1051/e3sconf/202124503050 ◽

2021 ◽

Vol 245 ◽

pp. 03050

Author(s):

Flora Chen

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Ovarian Cancer ◽

Tumor Suppressor ◽

Epithelial Cells ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Small Gtpase ◽

Intracellular Signaling Pathways ◽

Cancer Types

Rab 25 is a small GTPase belonging to the RAS (rat sarcoma) superfamily. It is expressed in epithelial cells only and serves as a regulator of various intracellular signaling pathways. As a key player in in cell regulation, Rab 25 has been shown by research to function mainly as an oncogene in various cancers including breast cancer and ovarian cancer. However, Rab 25 has also been reported to be a tumor suppressor in cancer types such as colorectal cancer. A lot of research has been done about Rab 25 in recent years. This review is an overview of Rab 25, focusing on their role in human diseases such as cancer.

Download Full-text