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Purpose: Carbonic anhydrase IX (CAIX) is a well‐established prognostic marker in breast cancer (BC). Nevertheless, this prognostic value is yet to be confirmed in BC subtypes. This study aims to investigate the prognostic effects of CAIX in oestrogen receptor (ER)‐negative (ER−) BCs and to establish pathways related to cytoplasmic CAIX expression in ER− and lymph node‐negative BCs. Methods: Immunohistochemistry was performed to identify the prognostic role of CAIX protein expression in ER− tissue microarrays (TMAs) (n = 191). CAIX‐positive samples (n = 37) were transcriptionally profiled by TempO‐Seq and analysed by STRING. Real‐time quantitative PCR (RT‐qPCR) analysis was used to validate differentially expressed genes. Results: Overexpression of cytoplasmic CAIX was an independent predictor of recurrence free survival, disease‐free survival and overall survival in ER− cohort. RNA transcriptomic analysis identified 10 significant genes in ER− cohort and 3 genes in the node‐negative group. The STRING database demonstrated a significant interaction between MUCL1 and GALNT6, which were linked with extracellular matrix organisation, degradation of the extracellular matrix and disease of glycosylation pathways. In the node‐negative group, SPNS2 is mainly involved in the sphingolipid de novo biosynthesis pathway. A significant correlation between cytoplasmic SphK1 and cytoplasmic hypoxia‐inducible factor‐1α was observed. Among the 10 genes, 7 genes (SERHL2, GALNT6, MUCL1, MMP7, PITX2, CEACAM6 and SPNS2) were selected, and their expression was quantitatively assessed by RT‐qPCR. The PCR data of these genes showed that SERHL2, GALNT6, MUCL1, PITX2, and SPNS2 mRNA levels were expressed in MDA‐MB‐231 BC cell lines at variable levels of hypoxic exposure. Conclusion: Cytoplasmic CAIX was independently associated with poor prognosis in ER− BC. Gene expression profiles shed light on the pathways and genes associated with hypoxia in ER− BC. In node‐negative patients, SPNS2 was of particular interest. [ABSTRACT FROM AUTHOR]

The prognostic significance of hypoxia markers, hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and carbonic anhydrase IX (CAIX), was investigated in estrogen receptor (ER)-positive breast cancer patients. Immunohistochemistry determined the expression of makers in two independent ductal ER-positive cohorts (Training set, n =373 and Validation set, n =285) and was related to clinicopathological parameters and disease-free survival (DFS). In the training cohort, nuclear HIF-1α (1) was independently associated with poorer DFS in luminal A tumors [hazard ratio (HR) = 0.53 95% confidence interval (CI): 0.30-0.94, p =0.030]. In the validation cohort, both HIF-1α (1) and CAIX were independently associated with decreased DFS in the entire cohort (HR = 1.85 95% CI: 1.10-3.11, p =0.019; HR = 1.74 95% CI: 1.08-2.82, p =0.023), in luminal A disease (HR = 1.98 95% CI: 1.02-3.83, p =0.042), and in luminal B disease (HR = 2.75 95% CI: 1.66-4.55, p <0.001), respectively. Taken together, elevated cytoplasmic HIF-1α (1) expression was an independent prognostic factor in luminal A disease, whereas CAIX was an independent prognostic factor in luminal B disease. Further work in large tissue cohorts is required.

Introduction: Hypoxia is a characteristic of many solid tumours and results in an increase in expression of HIF-1α. Many studies have investigated the prognostic value of HIF-1α expression in breast cancer (BC), however, the prognostic value remains unclear. Therefore, a systematic review and meta-analysis was undertaken to determine the prognostic value of HIF-1α in BC patients., Methods: The electronic databases PubMed and Web of science were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in BC patients. Review Manager version 5.4 was employed to analysis data from 30 eligible studies (containing 6201patients)., Results: High expression of HIF-1α was associated with poorer DFS and OS. There was an effect of survival analysis, study region, antibodies used, scoring and threshold methods on HIF-1α expression., Conclusion: HIF-1α overexpression was significantly associated with poorer DFS and OS in breast cancer patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)