Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications

Drosouni, Andrianna; Παναγοπούλου, Μαρία; Aidinis, Vassilis; Chatzaki, Εkaterini

doi:10.3390/cancers14215437

Cited by 11 publications

(4 citation statements)

References 117 publications

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“…If fact, analysis of data from TCGA demonstrate that ENPP2 is of one of the 66 most hypermethylated genes in stage 1-3 breast cancer [ 48 ]. Whether this methylation is a protective event of the host organism to suppress tumor development is unknown, but these studies demonstrate that despite breast cancer cells displaying the propensity to overexpress ATX, they are prevented from doing so even at early stages, and instead must rely on inducing ATX in the surrounding tumor stroma to induce LPA-mediated tumorigenesis [ 49 , 50 ].…”

Section: Insights Into Atx Production In the Breast Tumor Microenviro...mentioning

confidence: 99%

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

Benesch,

Tang,

Brindley

et al. 2024

World J Oncol

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Overcoming and preventing cancer therapy resistance is the most pressing challenge in modern breast cancer management. Consequently, most modern breast cancer research is aimed at understanding and blocking these therapy resistance mechanisms. One increasingly promising therapeutic target is the autotaxin (ATX)-lysophosphatidate (LPA)-lipid phosphate phosphatase (LPP) axis. Extracellular LPA, produced from albumin-bound lysophosphatidylcholine by ATX and degraded by the ecto-activity of the LPPs, is a potent cell-signaling mediator of tumor growth, invasion, angiogenesis, immune evasion, and resistance to cancer treatment modalities. LPA signaling in the post-natal organism has central roles in physiological wound healing, but these mechanisms are subverted to fuel pathogenesis in diseases that arise from chronic inflammatory processes, including cancer. Over the last 10 years, our understanding of the role of LPA signaling in the breast tumor microenvironment has begun to mature. Tumor-promoting inflammation in breast cancer leads to increased ATX production within the tumor microenvironment. This results in increased local concentrations of LPA that are maintained in part by decreased overall cancer cell LPP expression that would otherwise more rapidly break it down. LPA signaling through six G-protein-coupled LPA receptors expressed by cancer cells can then activate virtually every known tumorigenic pathway. Consequently, to target therapy resistance and tumor growth mediated by LPA signaling, multiple inhibitors against the LPA signaling axis are entering clinical trials. In this review, we summarize recent developments in LPA breast cancer biology, and illustrate how these novel therapeutics against the LPA signaling pathway may be excellent adjuncts to extend the efficacy of evolving breast cancer treatments.

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Section: Insights Into Atx Production In the Breast Tumor Microenviro...mentioning

confidence: 99%

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

Benesch,

Tang,

Brindley

et al. 2024

World J Oncol

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“…[2] Lysophosphatidic acid is a potent phospholipid mediator that elicits growth factor-like responses in most cell types, promoting cell growth, survival, differentiation, and motility. [3,4] Numerous studies have demonstrated that ENPP2 plays a vital role in tumor cell proliferation, metastasis, invasion, and angiogenesis [5] Aberrant ENPP2 expression has been reported in various malignant tumors, including pancreatic, [6] prostate, [7] breast, [8,9] ovarian, [10] glioblastoma multiforme, [11] lung, [12] and bladder cancers, [13] and is correlated with adverse clinical outcomes. Recent findings suggest that ENPP2 may contribute to the development of hepatitis B-induced HCC by enhancing ENPP2 secretion in liver cancer cells.…”

Section: Ectonucleotidementioning

confidence: 99%

High expression of ENPP2 is an independent predictor of poor prognosis in liver cancer

Ruan

Wei

et al. 2023

Medicine

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Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been identified as a potential biomarker in lung and prostate cancers; however, its expression and clinical relevance in hepatocellular carcinoma (HCC) remain incompletely understood. This study comprehensively assessed ENPP2 expression in pan-cancer using bioinformatics. We analyzed the expression of ENPP2 mRNA in primary liver cancer and adjacent tissues of patients with HCC using data from the TCGA database. Cox regression and Kaplan–Meier methods were used to identify clinicopathological factors associated with survival, and the diagnostic value of ENPP2 expression was evaluated using receiver operating characteristic curve analysis. We also validated our findings by performing real-time PCR on clinical liver cancer samples. Furthermore, we conducted gene set enrichment analysis using the Cancer Genome Atlas dataset to gain additional insights into the biological significance of ENPP2 in HCC. High ENPP2 expression in HCC patients is associated with gender and clinical stage, and is a significant prognostic factor for worse outcomes. ENPP2 expression is an independent risk factor for progression-free and disease-specific survival in both cohorts, suggesting its potential as an HCC biomarker. ENPP2’s diagnostic value in HCC patients was confirmed by the area under the receiver operating characteristic curve, which was 0.806. real-time PCR analysis validated the higher expression of ENPP2 in clinical liver cancer tissues. Gene set enrichment analysis identified pathways enriched in HCC patients with high ENPP2 expression, including those related to the cell cycle, MTOR and T cell receptor signaling, and phosphatidylinositol signaling systems. We have demonstrated that ENPP2 is highly expressed in HCC and is a potential independent molecular marker for the diagnosis and prognosis of HCC.

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“…ATX is highly expressed in lung cancer cells DMS273, ovarian cancer cells SKOV3, and colon cancer cells Colo320, as well as in most glioma cells, and the expression of ATX greatly increases the motility of tumor cells [ 14 ]. ATX is expressed in tumors such as non-small cell lung cancer, breast cancer, prostate cancer, liver cancer, thyroid cancer, and glioma, and is one of the 40 major upregulated genes associated with tumor migration [ 15 , 16 ]. Since the expression of ATX in tumor cells plays an important role in the occurrence and development of tumors, especially in tumor migration, ATX is considered an important target for tumor therapy.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner

Yang

Yin

et al. 2023

IJMS

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Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 cells, which could be rescued by the addition of LPA, suggesting that the induction of ATX during hypoxia promotes cancer cell migration through the ATX-LPA axis. Further studies showed that ATX expression was induced by HIF-2α through recruiting p300/CBP, which led to crotonylation but not acetylation of histone H3 in the ATX promoter region during hypoxia. Moreover, elevation of cellular histone crotonylation levels could induce ATX expression under normoxic conditions. In conclusion, our findings reveal that ATX is induced in SW480 cells during hypoxia by histone crotonylation in a HIF-2α-dependent manner, while as a novel mechanism of ATX expression regulation, the upregulation of ATX expression by histone crotonylation is not confined to hypoxia.

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Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications

Cited by 11 publications

References 117 publications

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

High expression of ENPP2 is an independent predictor of poor prognosis in liver cancer

Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner

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