ENPP3 expressed by HER2-positive breast cancer cells is associated with good prognosis by restraining epithelial-to-mesenchymal phenotype
Background Ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3/CD203c) is largely studied as a marker of mast cells and basophils. By depleting extracellular ATP, it prevents excessive activation of mast cells and basophils, hence reducing inflammation and allergic reactions. Recent findings have also shown that Enpp3 can deplete cGAMP, another molecule involved in STING activation and…
Recent studies have revealed that the expression of ENPP3 in HER2-positive breast cancer cells is linked to a positive prognosis, as it helps restrain the epithelial-to-mesenchymal phenotype. ENPP3, primarily studied for its role in mast cells and basophils, has been found to deplete cGAMP, a molecule involved in STING activation and IFN-mediated inflammation. Although its role in non-immune cells is still under investigation, this research provides valuable insights into its expression and implications in breast cancer.
To investigate the expression levels and prognostic value of Enpp3 in breast cancer, researchers conducted in silico analysis and evaluated ENPP3 expression in formalin-fixed, paraffin-embedded tumor samples through immunohistochemistry. Additionally, ENPP3 expression was assessed in mouse mammary cancer cell lines using western blots.
To further understand the role of Enpp3, researchers engineered a mouse-derived mammary cancer cell line to introduce a GFP sequence under the control of the Enpp3 promoter. By sorting GFP-positive and -negative cells and analyzing gene expression profiles, they identified pathways associated with Enpp3 expression.
Moreover, researchers created wild type and Enpp3 knockout cells and injected them into the fat pads of Wsh mice, which lack mast cells. The growth of the tumors was monitored and analyzed by immunohistochemistry. The results demonstrated that HER2-positive cells express higher levels of ENPP3 in breast cancer patients. In vitro models confirmed that HER2 expression and EGFR stimulation result in up-regulation of Enpp3.
The absence of Enpp3 in vivo was found to promote tumor growth and development of tumors with a marked epithelial-to-mesenchymal phenotype. Importantly, in a small cohort of HER2-positive breast cancer patients, ENPP3 expression was correlated with increased relapse-free survival.
Despite its potential immunosuppressive role, these findings suggest that ENPP3 expression is promoted by HER2 in breast cancer and is associated with a positive prognostic value.
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