Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Zhang, Yu; Li, Jun; Lai, Xing-Ning; Jiao, Xueqiao; Xiong, Junping; Xiong, Likuan

doi:10.3390/cells8020146

Cited by 46 publications

(35 citation statements)

References 188 publications

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“…MMP9 expression levels were positively associated with the expression of CDC42. CDC42 is a member of the Rho family of GTPases, which plays a role in many of the cellular processes that are associated with tumour progression, such as cell migration, proliferation, cytoskeletal control and vesicular trafficking [44]. A study conducted by Sipes and colleagues; revealed that, CDC42 deletion significantly reduced MMP9 activity.…”

Section: Discussionmentioning

confidence: 99%

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Joseph

Alsaleem

Orah

et al. 2020

Breast Cancer Res Treat

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Purpose MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC). Methods MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways. Results MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients' outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways. Conclusion This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted. Keywords MMP9 • Breast cancer • ECM remodelling • Prognosis Abbreviations BC Breast cancer BCSS BC-specific survival CI Confidence intervals DGE Differential gene expression ER Oestrogen HR Hazard ratio HER2 Human epidermal growth factor receptor 2 METABRIC Molecular taxonomy of breast cancer international consortium NPI Nottingham Prognostic Index PR Progesterone

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Section: Discussionmentioning

confidence: 99%

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Joseph

Alsaleem

Orah

et al. 2020

Breast Cancer Res Treat

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“…Besides being a predictive factor for tumor occurrence or for its progression, whether Rho GTPases pathways could be used as therapeutic targets is clearly an aspect that needs to be developed in the near future. Several drugs directly targeting Rho GTPases have been recently designed and different strategies such as preventing Rho GEF interaction or inhibiting effectors have been proposed [125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141]. However, based on the complex involvement of Rho GTPases and their regulators in NETs hypersecretion, as reviewed here, the development of proper strategies to target each specific tumor will be critical and will require a perfect knowledge of the mechanisms leading to the deregulation of the Rho pathways, as well as their consequences on tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

Streit

Brunaud

Vitale

et al. 2020

Cancers

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Neuroendocrine tumors (NETs) belong to a heterogeneous group of neoplasms arising from hormone secreting cells. These tumors are often associated with a dysfunction of their secretory activity. Neuroendocrine secretion occurs through calcium-regulated exocytosis, a process that is tightly controlled by Rho GTPases family members. In this review, we compiled the numerous mutations and modification of expression levels of Rho GTPases or their regulators (Rho guanine nucleotide-exchange factors and Rho GTPase-activating proteins) that have been identified in NETs. We discussed how they might regulate neuroendocrine secretion.

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“…Metastasis is a key factor influencing the prognosis of PC, and it is well-known that miRNAs can regulate the development, progression and metastasis of breast cancer ( 33 , 34 ). In PC, miRNAs have been found to affect tumor metastasis and function as biomarkers, and prognostic and therapeutic modulators of PC ( 35 – 38 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

et al. 2020

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MicroRNA (miR)-23b-3p plays an important role in tumor growth, proliferation, invasion and migration in pancreatic cancer (PC). However, the function and mechanistic role of miR-23b-3p in the development of PC remains largely unknown. In the present study, the miR-23b-3p levels in the serum of patients with PC were found to be elevated, and the phosphorylation levels of Janus kinase (JAK)2, PI3K, Akt and NF-κВ were found to be upregulated. In addition, miR-23b-3p was induced in response to interleukin-6 (IL-6), which is known to be involved in the progression of PC. Overexpression of miR-23b-3p, on the other hand, activated the JAK/PI3K and Akt/NF-κB signaling pathways in PC cells, as evidenced by miR-23b-3p-induced upregulation of phosphorylated (p-) JAK2, p-PI3K, p-Akt and p-NF-κВ, as well as the downregulation of PTEN; and these effects were found to be reversible by miR-23b-3p inhibition. Furthermore, miR-23b-3p was found to downregulate PTEN by directly targeting the 3'-untranslated region of PTEN mRNA. Notably, in an in vivo xenograft mouse model, overexpression of miR-23b-3p accelerated PC cell-derived tumor growth, activated the JAK/Akt/NF-κВ signaling pathway and promoted liver metastasis. In contrast, knockdown of miR-23b-3p suppressed tumor growth and metastasis as well as JAK/Akt/NF-κВ signaling activity. In vivo imaging of the mice further confirmed the metastasis promoting role of miR-23b-3p in PC. These results suggested that miR-23b-3p enhances PC cell tumorigenesis and metastasis, at least, partially via the JAK/PI3K and Akt/NF-κB signaling pathways. Therefore, targeting miR-23b-3p or the JAK/PI3K and Akt/NF-κB signalings may be potential therapeutic strategy against PC.

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Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Cited by 46 publications

References 188 publications

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways

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Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Cited by 46 publications

References 188 publications

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑&kappa;B signaling pathways

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MicroRNA‑23b‑3p promotes pancreatic cancer cell tumorigenesis and metastasis via the JAK/PI3K and Akt/NF‑κB signaling pathways