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Renewed interests in carbonic anhydrase IX in relevance to breast cancer treatment.

ABSTRACT: The highly proliferating cancerous cells can form permissive accommodating milieu - the so-called tumor microenvironment (TME). During the initiation of solid tumors, hypoxia plays a key role in glycolysis, which can trigger the anomalous overexpression of several enzymes and transporters involved in the metabolism of glucose. Of these, carbonic anhydrases (CAs), especially CAIX, together with other molecular machinery involved in the production/trafficking of acidic byproducts, play key roles in the regulation of intracellular and extracellular pH. CAIX, along with other molecular machinery of cancer cells such as Na+/H+ exchanger 1 (NHE1) and V-type H+-ATPase (V-ATPase), alkalinizes the tumor cells and maintains the acidic pH condition within the extracellular fluid of the TME. It facilitates the progression and metastasis of cancer and intensifies the migration and invasion of cancer cells. Thus, inhibition of CAIX can be considered a highly effective and promising therapeutic strategy in the treatment of aggressive tumors.

SUBMITTER: Dolatkhah M

PROVIDER: S-EPMC6879713 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Renewed interests in carbonic anhydrase IX in relevance to breast cancer treatment.

Dolatkhah Mitra M Omidi Yadollah Y

BioImpacts : BI 20190827 4

The highly proliferating cancerous cells can form permissive accommodating milieu - the so-called tumor microenvironment (TME). During the initiation of solid tumors, hypoxia plays a key role in glycolysis, which can trigger the anomalous overexpression of several enzymes and transporters involved in the metabolism of glucose. Of these, carbonic anhydrases (CAs), especially CAIX, together with other molecular machinery involved in the production/trafficking of acidic byproducts, play key roles i ...[more]

PMID: 31799155

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Project description:BackgroundThe effect of extracellular microenvironment (hypoxia and pH) has been regarded as a key hallmark in cancer progression. The study aims to investigate the effects of carbonic anhydrase IX (CAIX), a key hypoxia-inducible marker, in triple-negative breast cancer (TNBC) in correlation with clinicopathological parameters and predicting survival outcomes.MethodsA total of 323 TNBC cases diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 2003 to 2013 were used. Immunohistochemical staining (IHC) was performed using CAIX antibody and digital mRNA quantification was performed using NanoString assays. CAIX membranous expression was correlated with clinicopathological parameters using Chi-squared test or Fisher's exact tests. Disease-free survival (DFS) and overall-survival (OS) were estimated using Kaplan-Meier analysis and compared between groups with the log-rank test.ResultsForty percent of TNBCs were observed to express CAIX protein and demonstrated significant association with larger tumour size (P = 0.002), higher histological grade (P < 0.001), and significantly worse disease-free survival (DFS) and overall survival (OS) (after adjustment: HR = 2.99, 95% CI = 1.78-5.02, P < 0.001 and HR = 2.56, 95% CI = 1.41-4.65, P = 0.002, respectively). Gene ontology enrichment analysis revealed six significantly enriched cellular functions (secretion, cellular component disassembly, regulation of protein complex assembly, glycolytic process, cellular macromolecular complex assembly, positive regulation of cellular component biogenesis) associated with genes differentially expressed (CAIX, SETX, WAS, HK2, DDIT4, TUBA4α, ARL1). Three genes (WAS, SETX and DDIT4) were related to DNA repair, indicating that DNA stability may be influenced by hypoxia in TNBC.ConclusionsOur results demonstrate that CAIX appears to be a significant hypoxia-inducible molecular marker and increased CAIX protein levels are independently associated with poor survival in TNBC. Identification of CAIX-linked seven gene-signature and its relationship with enriched cellular functions further support the implication and influence of hypoxia-mediated CAIX expression in TNBC tumour microenvironment.

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Renewed interests in carbonic anhydrase IX in relevance to breast cancer treatment.

Publications

Renewed interests in carbonic anhydrase IX in relevance to breast cancer treatment.

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