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Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1alpha, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.

Original publication

DOI

10.1038/sj.bjc.6604844

Type

Journal article

Journal

Br J Cancer

Publication Date

27/01/2009

Volume

100

Pages

405 - 411

Keywords

Adult, Aged, Aged, 80 and over, Antigens, Neoplasm, Antineoplastic Agents, Biomarkers, Tumor, Breast Neoplasms, Carbonic Anhydrase IX, Carbonic Anhydrases, Dioxygenases, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Immunoenzyme Techniques, Middle Aged, Mixed Function Oxygenases, Neoplasm Invasiveness, Neoplasm Staging, Procollagen-Proline Dioxygenase, Prognosis, Repressor Proteins, Survival Rate, Transcription Factors